Thiazole derivative and leukotriene antagonist containing the same as the effective ingredients

ABSTRACT

Disclosed are a thiazole derivative represented by the following formula, a pharmaceutically acceptable salt thereof and leukotriene antagonist containing the same as the active ingredients: ##STR1## wherein R 1  and R 2  each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a lower alkoxycarbonyl group or a substituted or unsubstituted phenyl group or cooperatively represent a tetramethylene group corresponding to a fused cyclohexane ring or a butadienylene group which is unsubstituted or substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1 to 3 carbon atoms corresponding to a fused benzene ring; R 3 , R 4 , R 5  and R 6  each independently represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, an alkyl group having 1 to 3 carbon atoms or a halogen atom; A represents a linking group having 2 to 4 chain members; B represents a linking group having 2 to 5 chain members; and Q represents a carboxyl group, a lower alkoxy group, a hydroxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms or a 5-tetrazolyl group.

This application is a Continuation of application Ser. No. 06/919,497,filed on Oct. 16, 1986, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a novel thiazole derivative having leukotrieneantagonistic action and a leukotriene antagonist containing the same asthe active ingredient.

For prophylaxis or therapy of allergic diseases, there are the methodwhich inhibits liberation of the mediator of anaphylaxis and the methodwhich permits an antagonist to act on the mediator liberated. Disodiumcromoglycate [The Merck Index, ninth edition 2585 (1976)] and Tranirast[Journal of Japanese Pharmacology, 74, 699 (1978)] are typical drugsbelonging to the former and those belonging to the latter may includedrugs antagonistic to hystamine which is one of the mediators ofalllergic reactions such as diphenehydramine, chlorophenylamine,astemizole, terfenadine, clemastine, etc., as well known drugs. However,a substance which cannot be antagonized with an anti-hystamine agent,namely SRS (Slow Reacting Substance) has been suggested to be liberatedfrom the lung of a bronchial asthma patient [Progr. Allergy, 6, 539(1962)], and recently these SRS [leukotriene C₄ (LTC₄), leukotriene D₄(LTD₄) and leukotriene E₄ (LTE₄)] are comprehensively called SRS [Proc.Natl. Acad. Sci. U.S.A., 76, 4275 (1979) and 77, 2014 (1980); Nature,285, 104 (1980)] and considered as the important factor participating inhuman asthma attack [Proc. Natl. Acad. Sci. U.S.A., 80, 1712 (1983)].

Some leukotriene antagonists have been known in patents or literatures.For example, there have been known FPL-55712 [Agents and Actions, 9, 133(1979)] represented by the following formula: ##STR2## KC-404 [Jap. J.Pharm., 33, 267 (1983)] represented by the following formula: ##STR3##KZ-111 [Chem. Abst, registration number 72637-30-0] represented by thefollowing formula: ##STR4## and the compound represented by thefollowing formula (U.S. Pat. No. 4,296,129): ##STR5## wherein R₁represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms ora group represented by represented by the following formula: ##STR6##(wherein R₃ and R₄ each represent an alkyl group having 1 to 3 carbonatoms); R₂ represents an alkyl group having 8 to 15 carbon atoms or acycloalkyl group having 6 to 12 carbon atoms; R₅ and R₆ each represent ahydrogen atom or a methyl group. However, none of these have beenclinically applied.

On the other hand, of the thiazole derivatives, as the compounds inwhich the 2-position of thiazole and the phenyl group are bonded through2 to 4 atoms, there have been known a large number of compounds such asthe compound (Japanese Unexamine Patent Publication No. 22460/1973)represented by the formula: ##STR7## the compound represented by thefollowing formula [Farmaco. Ed. Sci, 21, 740 (1966)]: ##STR8## thecompound represented by the following formula (German Pat. No. 31 48291): ##STR9## and the compound represented by the following formula(Japanese Unexamined Patent Publication No. 16871/1984): ##STR10##However, in any of these literatures or patents, nothing is mentionedabout the leukotriene antagonistic action.

The present inventors have sought after compounds having antagonisticaction to leukotriene and effective as the therapeutical medicine forvarious diseases caused by leukotriene, and consequently found that anovel thiazole derivative has excellent leukotriene antagonistic actionto accomplish the present invention.

SUMMARY OF THE INVENTION

The thiazole derivative of the present invention is a compoundrepresented by the following formula (I): ##STR11## wherein R₁ and R₂each independently represent a hydrogen atom, an alkyl group having 1 to8 carbon atoms, a lower alkoxycarbonyl group or a substituted orunsubstituted phenyl group or taken together represent a tetramethylenegroup corresponding to a fused cyclohexane ring or a butadienylene groupwhich is unsubstituted or substituted with a halogen atom, a loweralkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1 to3 carbon atoms corresponding to a fused benzene ring; R₃, R₄, R₅ and R₆each independently represent a hydrogen atom, a hydroxyl group, a loweralkoxy group, an alkyl group having 1 to 3 carbon atoms or a halogenatom; A represents a linking group having 2 to 4 chain members; Brepresents a linking group having 2 to 5 chain members; and Q representsa carboxyl group, a lower alkoxy group, a hydroxyl group, analkoxycarbonyl group having 2 to 6 carbon atoms or a 5-tetrazolyl group.

DETAILED DESCRIPTION OF THE INVENTION

In the above formula (I), the alkyl group having 1 to 3 carbon atoms mayinclude methyl, ethyl, propyl and isopropyl. The alkyl group having 1 to8 carbon atoms may include, in addition to the alkyl groups having 1 to3 carbon atoms as mentioned above, straight and branched aliphaticgroups having 4 to 8 carbon atoms such as butyl, isobutyl, sec-butyl,t-butyl, amyl, isoamyl, sec-amyl, sec-isoamyl (1,2-dimethylpropyl),t-amyl (1,1-dimethylpropyl), hexyl, isohexyl (4-methylpentyl), sec-hexyl(1-methylpentyl), 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1,2,2-trimethylpropyl, heptyl, isoheptyl(5-methylhexyl), 2,2-dimethylpentyl, 3,3-dimethylpentyl,4,4-dimethylpentyl, 1,2dimethylpentyl, 1,3-dimethylpentyl,1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl,1,1,3-trimethylbutyl, octyl, isooctyl (6-methylheptyl), sec-octyl(1-methylheptyl) and t-octyl (1,1,3,3-tetramethylbutyl) group, etc. Thelower alkoxy group may include straight and branched alkoxy groupshaving 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy andisopropoxy group, etc. The lower alkoxy carbonyl group may includestraight and branched alkoxycarbonyl groups having 2 to 4 carbon atomssuch as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andisopropoxycarbonyl group. The alkoxy carbonyl group having 2 to 6 carbonatoms may include, in addition to the lower alkoxycarbonyl group asmentioned above, alkoxycarbonyl groups having 5 to 6 carbon atoms suchas butoxycarbonyl group and amyloxycarbonyl group and isomer-substitutedgroups of these. Examples of the halogen atom may include fluorine atom,chlorine atom, bromine atom and iodine atom. As the substituent on thesubstituted phenyl group in the definition of R₁ and R₂, there may beemployed, for example, the alkyl group having 1 to 3 carbon atoms, loweralkoxy group, lower alkoxycarbonyl group and halogen atom as mentionedabove. As the linking group in the definition of A, any group having 2to 4 atoms as the chain member constituting the linking group may beused, but it should particularly preferably contain carbon atom, oxygenatom, and nitrogen atom. Examples of such a linking group may include--CH═CH--, --CH₂ CH₂ --, --OCH₂ --, --NHCH₂ --, --CONH--,--CH═CH--CONH--, --CH₂ OCH₂ --, more preferably --CH═CH--, --CH₂ CH₂ --.As the linking group in the definition of B, any group having 2 to 5atoms in the chain group constituting the linking group may be used, butit should particularly preferably contain carbon atom, oxygen atom andnitrogen atom. Examples of such a linking group may include --(CH₂)_(n)--CONH-- (wherein n represents an integer of 0-3), --(CH₂)_(n) --NH--(wherein n represents an integer of 1-4), --(CH₂)_(n) --O-- (wherein nrepresents an integer of 1-4), --(CH₂)_(n) -- (wherein n represents aninteger of 2-5), ##STR12## wherein R₇ and R₈ each independentlyrepresent a hydrogen atom or an alkyl group having 1 to 3 carbon atomsas defined above), ##STR13## (wherein R₇ and R₈ have the same meaningsas defined above), ##STR14## (wherein R₇ and R₈ have the same meaningsas defined above), ##STR15## (wherein R₉, R₁₀, R₁₁ and R₁₂ eachindependently represent a hydrogen atom, a phenyl group or an alkylgroup having 1 to 6 carbon atoms), ##STR16## (wherein R₉, R₁₀, R₁₁ andR₁₂ have the same meanings as defined above), ##STR17## (wherein R₉ andR₁₁ have the same meanings as defined above), ##STR18## (wherein R₁₀ andR₁₂ have the same meanings as defined above), ##STR19## (wherein R₁₀ andR₁₂ have the same meanings as defined above), ##STR20## (wherein R₁₀ andR₁₂ have the same meanings as defined above), ##STR21## (wherein R₁₀ andR₁₂ have the same meanings as defined above), ##STR22## (wherein R₁₀ andR₁₂ have the same meanings as defined above), ##STR23## (wherein R₁₀ andR₁₂ have the same meanings as defined above), ##STR24## (wherein R₁₀ andR₁₂ have the same meanings as defined above), ##STR25## (wherein R₁₀ andR₁₂ have the same meanings as defined above), ##STR26## (wherein R₁₁ andR₁₂ have the same meanings as defined above), ##STR27## (wherein R₁₁ andR₁₂ have the same meanings as defined above), more preferably ##STR28##(wherein R₁₁ and R₁₂ each represent a hydrogen atom and R₉ and R₁₀ eachindependently represent an alkyl group having 1 to 6 carbon atoms).

The thiazole derivative of the present invention is not limited to aspecific isomer, but includes all of geometric isomers, steric isomers,optical isomers and their mixtures such as racemic mixture.

The thiazole derivative of the present invention can be synthesizedaccording to various methods.

For example, in the above formula (I), the compound wherein the linkinggroup B is bonded through a nitrogen atom to the benzene ring can besynthesized according to the synthetic routes [A]-[C]. ##STR29##

In the synthetic routes, R₁, R₂, R₃, R₄, R₅, R₆ and A have the samemeanings as defined above, B₃ represents a direct bond or a linkinggroup having 1 to 3 chain members, B₄ represents a linking group having1 to 4 chain members, M represents an alkali metal atom, X represents ahalogen atom and R₁₃ represents an alkyl group having 1 to 5 carbonatoms.

The aniline derivative (II) used as the starting material can besynthesized according to the known method [Tetrahedron Letters, 25, 839(1984)].

In the synthetic route [A], the aniline derivative (II) is allowed toreact with 0.8 to 2 equal amounts of a cyclic acid anhydride to obtainthe compound (Ia) (step [A-1]). As the reaction solvent, there may beemployed aromatic hydrocarbons such as toluene, benzene, etc.; ethertype solvent such as ethyl ether, dioxane, tetrahydrofuran, etc.;halogenated hydrocarbons such as chloroform, dichloromethane, etc. Thisreaction may be practiced at a temperature from under ice-cooling to theboiling point of the solvent, particularly preferably from roomtemperature to 60° C. The compound (Ia) can be converted to an alkalimetal salt (Ib) by the reaction with a carbonate, a hydrogen carbonateor a hydroxide of the corresponding alkali metal in a hydrous alcoholicsolvent (step [A-2]). Further, the compound (Ib) can be allowed to reactwith 1 to 3 equivalents of an alkylating agent such as an alkyl halideor an alkyl sulfonate, etc., in a non-protonic polar solvent such asdimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide triamide,etc., at 0° to 100° C. to be alkylated and converted to a carboxylicacid ester (Ic) (step [A-3]).

In the synthetic route [B], the compound (II) can be acylated by thereaction with a carboxylic acid monoester monohalide in the presence ofan organic base such as pyridine, triethylamine, etc., or an inorganicbase such as potassium carbonate, sodium hydrogen carbonate, etc., at0°-100° C. to synthesize the compound (Ic) (step [B-1]). As the reactionsolvent, there may be used aromatic hydrocarbons, ether type solvents,halogenated hydrocarbons or non-protonic polar solvents. The compound(Ic) can be hydrolyzed in a conventional manner in a hydrous alcoholicsolvent with an alkali metal type inorganic base such as sodiumhydroxide, potassium carbonate, etc., to be readily converted to thecompound (Ib) (step [B-2]). Also, after the above hydrolysis, theproduct can be treated with a mineral acid to obtain a free carboxylicacid (Ia) (step [B-3]).

In the synthetic route [C], the compound (II) can be allowed to reactwith a ω-halocarboxylic acid ester in the presence of an organic basesuch as triethylamine, pyridine, etc., in an aromatic hydrocarbon type,ether type or halogenated hydrocarbon type solvent at a temperature from0° C. to the boiling point of the solvent to effect N-alkylation andresult in synthesis of the compound (Id) (step [C-1]). The compound (Ie)can be synthesized according to the same method as in the step [B-3](step [C-2]), and the compound (If) can be synthesized in the samemanner as in the step [A-2] or the step [B-2] (step [C-3], step [C-4]).

In the above formula (I), the compound wherein the linking group B isbonded through an oxygen atom to the benzene ring can be synthesizedaccording to the synthetic route [D] shown below. ##STR30##

In the above synthetic route, R₁, R₂, R₃, R₄, R₅, R₆, R₁₃, A, B₄, M andX have the same meaning as defined above.

The phenol derivative (III) used as the starting material can besynthesized according to the known method [Journal of MedicinalChemistry, 25, 1378 (1982)].

By O-alkylation of the compound (III) with a ω-halocarboxylic acid esterin a solvent of ketone type such as acetone, methyl ethyl ketone, etc.,or alcohol type, in the presence of an inorganic base such as potassiumcarbonate, sodium hydrogen carbonate, etc., at a temperature from 0° C.to the boiling point of the solvent, the phenylether compound (Ig) canbe synthesized (step [D-1]). The compound (Ih) can be obtained from thecompound (Ig) similarly as in the step [B-2] (step [D-2]), and thecompound (Ii) can be obtained from the compound (Ih) according to thesame method as in the step [A-2] (step [D-3]), or from the compound (Ig)in the same manner as in the step [B-2] (step [D-4]).

In the above formula (I), the compound when the linking group A is avinylene group can be synthesized according to the synthetic route [E]shown below. ##STR31##

In the above synthetic route, R₁, R₂, R₃, R₄, R₅, R₆, R₁₃ B and M havethe same meanings as defined above. The benzaldehyde derivative [IV]used as the starting material can be synthesized according to the knownmethod [Journal of Medicinal Chemistry, 25, 1378 (1982)].

The compound (Ij) can be obtained according to the dehydratingcondensation reaction by heating the benzaldehyde derivative (IV) and a2-methylthiazole in acetic anhydride under nitrogen gas stream to100°-200° C. (step [E-1]). Hydrolysis of the compound (Ij) in the samemanner as in the step [B-3] gives the compound (Ik) (step [E-2]). Fromthe compound (Ik), an alkali metal salt (Il) can be obtained in the samemanner as in the step [A-2] (step [E-3]). The alkali metal salt (Il) canbe obtained also by treating similarly the compound (Ij) as in the step[B-2] (step [E-4]).

The compound (I) of the present invention is characterized by having amarked leukotriene antagonistic action.

More specifically, when the antagonistic action to SRS was tested invitro by use of an extirpated ileum of a guinea pig for the compound ofthe present invention, it has been found to have a selectiveantagonistic action for SRS even at an extremely low concentration. Whenfurther detailed LTD₄ antagonistic test was conducted by use of a guineapig for some of the compounds of the present invention which haveexhibited strong action in vitro test, it has been found that they caninhibit remarkably the asthmatic symptoms induced by LTD₄.

The leukotriene antagonist of the present invention contains thecompound represented by the above formkla (I) or its pharmaceuticallyacceptable salt as the active ingredient together with a solid or liquidcarrier or diluent for medicine, namely additives such as excepients,stabilizers, etc. When the compound (I) has a carboxylic group,preferable salts are non-toxic salts which are pharmaceuticallyacceptable such as alkali metal salts and alkaline earth metal saltssuch as sodium salts, potassium salts, magnesium salts, calcium salts oraluminum salts. It is similarly preferable to use adequate non-toxicamine salts such as ammonium salts, lower-alkylamine [e.g.triethylamine] salts, hydroxy lower-alkylamine [e.g.2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,tris(hydroxymethyl)aminomethane or N-methyl-D-glucamine] salts,cycloalkylamine [e.g. dicyclohexylamine] salts, benzylamine [e.g.N,N'-dibenzylethylenediamine] salts and dibenzylamine salts. In view ofthe basicity of the thiazole ring of the compound (I) of the presentinvention, preferable salts may include non-toxic salts such ashydrochlorides, methanesulfonates, hydrobromides, sulfates, phosphates,fumarates, succinates, etc. These salts are water-soluble and hence mostpreferable when used for injections. In said leukotriene antagonist, theproportion of the active ingredient to the carrier component in therapymay be variable between 1 wt. % to 90 wt. %. The leukotriene antagonistmay be administered orally in the dosage form such as granules, fineparticles, powders, tablets, hard capsules, soft capsules, syrup,emulsion, suspension or solution, or alternatively administeredintravenously, intramascularly or subcutaneously as injections. Also, itcan be used as topical administration preparation to rectum, nose, eye,lung in the dosage form such as suppository, collunarium, eye drops orinhalent. Further, it can be used in the form of powder for injectionwhich is to be formulated when used. It is possible to use an organic orinorganic, solid or liquid carrier or diluent for medicine suitable fororal, rectal, parenteral or local administration for preparation of theleukotriene antagonist of the present invention. Examples of theexcepient to be used in preparation of a solid preparation may includelactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calciumcarbonate, etc. Liquid preparations for oral administration, namely,emulsion, syrup, suspension, solution, etc., contain inert diluentsgenerally employed such as water or vegetable oils, etc. Thesepreparations can contain auxiliary agents other than inert diluents suchas humectants, suspension aids, sweeteners, aromatics, colorants orpreservatives. It may also be formulated into a liquid preparation whichis contained in capsules of absorbable substances such as gelatin. Asthe solvent or suspending agent to be used for production ofpreparations for parentheral administration, namely injections,suppositories, collunarium, eye drops, inhalent, etc., there may beemployed, for example, water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin, etc. As the base to be used forsuppository, there may be included, for example, cacao fat, emulsifiedcacao fat, laurine fat, Witepp sol, etc. The preparations can beprepared according to conventional methods.

The clinical dose, when used by oral administration, may be generally0.01 to 1000 mg/day as the compound of the present invention for humanadult, preferably 0.01 to 100 mg, but it is more preferable to increaseor decrease suitably the dose depending on the age, condition of diseaseand symptoms. The above mentioned dose per day of the leukotrieneantagonist may be administered once per day or in 2 or 3 divided dosesper day at suitable intervals, or intermittently.

On the other hand, when used as an injection, it is preferable toadminister continuously or intermittently 0.001 to 100 mg/administrationas the compound of the present invention to human adult.

According to the present invention, a novel thiazole derivative havingremarkable leukotriene antagonistic action can be provided. Saidthiazole derivative is useful as the leukotriene antagonist forprophylaxis and therapy of various diseases in which leukotrieneparticipates.

The present invention is described in more detail by referring toSynthesis examples, Examples and Test examples, but these are notintended to limit the scope of the present invention at all. InSynthesis examples and Examples, the symbols of "IR", "TLC", "NMR" and"MS" represent "infrared-absorption spectrum", "thin layerchromatography", "nuclear magnetic resonance spectrum" and "massanalysis", respectively, the proportion of the solvent written at thesite of separation by chromatography indicating volume ratio, thesolvent in the parenthesis of "TLC" indicating a developing solvent,"IR" being measured according to the KBr tablet method unless otherwisespecifically noted, and the solvent in the parenthesis of "NMR"indicating the measurement solvent.

SYNTHESIS EXAMPLE 1 Synthesis of 4-isopropyl-2-methylthiazole

To a solution of 25 g of 3-methyl-2-butanone dissolved in 174 ml ofmethanol, 15.8 ml of bromine was added dropwise while temperature of thereaction mixture was maintained within the range of 0° to 5° C., andfurther the mixture was stirred at 10° C. for 1 hour. Then, 87 ml ofwater was added and the mixture was stirred at room temperatureovernight. After completion of the reaction, the reaction mixture wasextracted with ethyl ether, the extract was washed with 10% aqueouspotassium carbonate solution and dried over calcium chloride, followedby evaporation of the solvent to give 53.2 g of a crude product of1-bromo-3-methyl-4-butanone as colorless liquid. Further, withoutpurification, 43.2 g of the above bromoketone was dissolved in 100 ml ofethanol and the solution was added at room temperature to a solution of19.7 g of thioacetamide dissolved in 150 ml of ethanol. After thereaction was completed by refluxing for 2.5 hours, ethanol wasevaporated under reduced pressure and the residue was ice-cooled toprecipitate crystals. The crystals are washed with ethyl ether, pouredinto 250 ml of an aqueous saturated sodium hydrogen carbonate solution,free bases were extracted with n-hexane, followed by drying overanhydrous magnesium sulfate and concentration under reduced pressure togive 27.1 g (yield 73%) of the title compound as pale brown liquid.

IR (film): ν=2950, 1510, 1450, 1165, 730 cm⁻¹.

NMR (CDCl₃): δ=1.30(6H,d), 2.68(3H,s),

3.07(1H,m), 6.67(1H,s).

SYNTHESIS EXAMPLE 2 Synthesis of 4-isopropyl-2-(trans-3-nitrostyryl)thiazole

To 11.3 ml of acetic anhydride were added 29.0 g of 3-nitrobenzaldehydeand 27.1 g of 4-isopropyl-2-methylthiazole and the reaction was carriedout under nitrogen gas stream at 170° C. for 23 hours. After completionof the reaction, low boiling materials were evaporated under reducedpressure and the residue was recrystallized from ethyl ether-n-hexane togive 16.8 g (yield 32%) of the title compound as yellowish whitecrystals.

NMR (CDCl₃): δ=1.34(6H,d), 3.12(1H,m),

6.86(1H,s), 7.2-8.4(6H,m).

IR: ν=1625, 1590, 1435, 1305, 1210, 945,

770 cm⁻¹.

SYNTHESIS EXAMPLE 3 Synthesis of2-(3-nitrophenyl)methoxymethylbenzothiazole

A mixture of 1.60 g of 3-nitrobenzyl chloride, 1.3 g of2-hydroxymethylbenzothiazole and 0.54 of potassium carbonate in 20 ml ofacetone was stirred at room temperature for 1.5 hours and then refluxedfor 30 minutes. After evaporation of acetone under reduced pressure, theresidue was dissolved in ethyl acetate, washed with water and dried overmagnesium sulfate, followed by evaporation of the solvent under reducedpressure. The residue was purified through a silica gel columnchromatography by use of ethyl ether-n-hexane to obtain 1.7 g (yield73%) of the title compound.

IR: ν=1520, 1340, 1090, 800, 766, 725 cm⁻¹.

NMR (CDCl₃): δ=4.65(2H,s), 4.90(2H,s), 7.1-8.2

(8H,m).

SYNTHESIS EXAMPLE 4 Synthesis of2-[2-(3-hydroxyphenyl)ethyl]benzothiazole

A mixture of 6.0 g of 2-(trans-3-hydroxystyryl) benzothiazole and 0.5 gof 5% palladium-carbon in 80 ml of ethanol was stirred under hydrogengas stream under normal pressure at 50° to 60° C. for 3 hours. Aftercompletion of the reaction, the catalyst was filtered off and thefiltrate was evaporated under reduced pressure to obtain 5.5 g (yield92%) of the title compound as pale gray crystals.

IR: ν=3050, 1580, 1480, 1280, 760 cm⁻¹.

m.p.: 129°-130° C.

SYNTHESIS EXAMPLE 5 Synthesis of2-(trans-3-hydroxystyryl)-4ethyl-5-methylthiazole

An amount of 3.0 g of 2-(trans-3-aminostyryl)-4-ethyl-5-methylthiazolewas added to 18 ml of 20% hydrochloric acid and to the mixture was addeddropwise slowly 3 ml of an aqueous solution of 0.86 g of sodium nitritewhile maintaining the inner temperature at 4° to 5° C. After the mixturewas stirred at the above temperature for 1.5 hours, the reaction mixturewas added into 50 ml of boiling water over 20 minutes. After the mixturewas cooled to room temperature, the precipitates formed were collectedby filtration, washed with aqueous saturated sodium hydrogen carbonatesolution and with water, followed by drying under reduced pressure. Thecrude product was washed with toluene and dried under reduced pressureto obtain 2.1 g (yield 70%) of the title compound.

m.p.: 161°-162° C.

IR: ν=1620, 1598, 1575, 1215, 950, 778 cm⁻¹.

SYNTHESIS EXAMPLE 6 (1) Synthesis of2-(trans-3-hydroxystyryl)benzothiazole

A mixture of 25 g of 3-hydroxybenzaldehyde, 36.6 g of2-methylbenzothiazole, 38.8 ml of acetic anhydride and 7.7 ml of formicacid was heated at 120° C. for 25 hours. The low boiling materials wereevaporated together with toluene under reduced pressure, and the residuewas added to 150 ml of methanol and refluxed with addition of 3 g ofpotassium carbonate for 1 hour. After cooled to room temperature, themixture was filtered and filtrate was concentrated. The crude productformed was washed with methanol and ethyl ether and dried under reducedpressure to obtain 20.6 g (yield 40%) of the title compound.

m.p.: 210°-211° C.

IR: ν=1620, 1570, 1190, 1145, 935, 750 cm⁻¹.

(2)

The operation similar to (1) was conducted to obtain2-(trans-3-hydroxystyryl)-4-phenylthiazole (yield 21%).

m.p.: 150°-151° C.

IR: ν=3450, 1580, 1280, 950, 730 cm⁻¹.

SYNTHESIS EXAMPLE 7 Synthesis of ethyl 5-(3-cyanophenyl-4pentenoate)

An amount of 0.66 g of 60% sodium hydride was added to 14 ml ofanhydrous dimethyl sulfoxide and the mixture was heated under nitrogengas stream to 75° to 80° C. to form dimsyl anions. After cooled to roomtemperature, the mixture was added to a solution of 6.3 g of3-ethoxycarbonylpropyltriphenylphosphonium bromide in 20 ml of anhydrousdimethyl sulfoxide. The mixture was stirred at room temperature for 5minutes and a solution of 1.5 g of 3-cyanobenzaldehyde in 4 ml ofanhydrous dimethyl sulfoxide, followed by stirring at room temperaturefor 1.5 hours. After completion of the reaction, 5% hydrochloric acidwas added to stop the reaction, and the reaction mixture was extractedwith toluene. After evaporation of the solvent under reduced pressure,the residue was purified through silica gel column chromatography by useof ethyl ether-n-hexane to obtain 0.94 g (yield 36%) of the titlecompound as colorless oily product.

IR (film): ν=1725, 1245, 1180, 1150, 960,

785 cm⁻¹.

NMR (CCl₄): δ=1.25(3H,t), 2.2-2.8(4H,m),

4.09(2H,q), 6.2-6.6(2H,m),

7.3-7.7(4H,m).

SYNTHESIS EXAMPLE 8 Synthesis of ethyl 5-(3-formylphenyl)pentanoate

An amount of 660 mg of ethyl 5-(3-cyanophenyl)-4-pentenoate and 60 mg of5% palladium-carbon were added into 6 ml of ethanol and catalyticreduction was carried out under hydrogen gas stream at room temperaturefor 18 hours. After the catalyst was filtered off, the filtrate wasevaporated under reduced pressure and 600 mg of the crude product wasused for the subsequent reaction.

Into a suspension of 986 mg of anhydrous stannous chloride in anhydrousethyl ether was introduced hydrogen chloride gas for 2 minutes toprovide a uniform solution. Next, 600 mg of the above saturatedcarboxylic acid ester dissolved in 4 ml of ethyl ether was added andhydrogen chloride gas was introduced again for 1 minute, followed bystirring at room temperature for 5 hours. Subsequently, each 5 ml ofethyl ether and water was added and after stirred at room temperaturefor 1 hour, the organic layer was extracted with toluene. After dryingover magnesium sulfate, the solvent was evaporated under reducedpressure and the residue was purified through silica gel columnchromatography by use of ethyl ether-n-hexane to give 460 mg (yield 68%)of the title compound as colorless oily product.

IR (film): ν=1725, 1690, 1440, 1365, 1235, 1180,

1020, 790 cm⁻¹.

NMR (CCl₄): δ=1.20(3H,t), 1.4-1.9(4H,m),

2.0-2.9(4H,m), 4.5(2H,q),

7.2-7.8(4H,m), 9.88(1H,s).

SYNTHESIS EXAMPLE 9 Synthesis of2-[trans-3-(3-cyanopropylamino)styryl]benzothiazole

To 50 ml of toluene were added 2.02 g of triethylamine and 5.04 g of2-(trans-3-aminostyryl)benzothiazole at room temperature, and then 2.96g of 4-bromobutyronitrile was added to carry out the reaction at 110° C.for 7 hours. After completion of the reaction, the reaction mixture wasextracted with ethyl acetate. After evaporation of the solvent underreduced pressure, the residue was purified through silica gel columnchromatography by use of ethyl acetate-ethyl ether-n-hexane (2:5:5) togive 2.55 g (yield 40%) of the title compound as colorless oily product.

m.p.: 97°-98° C.

IR: ν=3400, 2250, 1600, 950, 760 cm⁻¹.

SYNTHESIS EXAMPLE 10 Synthesis of 4-isopropyl-2-(trans-3-aminostyryl)thiazole

To a solution of 16.8 g of 4-isopropyl-2-(trans-3-nitrostyryl)thiazoledissolved in 60 ml of ethanol was added a solution of 48.4 g of stannouschloride dihydrate in 60 ml of ethanol and the mixture was refluxed for1.5 hours. After the reaction mixture was cooled to room temperature,the mixture was adjusted to pH 13 with addition of 30% aqueous sodiumhydroxide solution and then the basic portion was extracted with the useof ethyl acetate and dried over magnesium sulfate, followed byevaporation of the solvent under reduced pressure. The solid residueformed was recrystallized from ethyl ether-n-hexane to obtain 7.1 g(yield 47%) of the pale yellowish white title compound.

m.p.: 62°-63° C.

IR: ν=3430, 3300, 1600, 1580, 960, 780, 740 cm⁻¹.

NMR (CDCl₃): δ=1.32(6H,d), 2.90-3.4(1H,m), 3.70(2H,s), 6.5-7.3(7H,m).

SYNTHESIS EXAMPLE 11 Synthesis of various thiazole derivatives

By carrying out the treatment similarly as in Synthesis example 10,various thiazole derivatives shown as Nos. 1-32 and 36-38 in Table 1were obtained.

SYNTHESIS EXAMPLE 12 Synthesis of2-[2-(3-aminophenyl)ethyl]-4-ethyl-5-methylthiazole

An amount of 1.0 g of 2-(3-aminostyryl)-4-ethyl-5-methylthiazole and 200mg of 5% palladium-carbon were added to 20 ml of ethanol and catalyticreduction was carried out in a hydrogen gas atmosphere at roomtemperature and normal pressure for 12 hours. After the reaction mixturewas filtered, the solvent was evaporated under reduced pressure to give0.90 g (yield 90%) of the title compound as pale yellow crystals.

m.p.: 64°-65° C.

IR: ν=3410, 1590, 1300, 1120, 950, 760 cm⁻¹.

SYNTHESIS EXAMPLE 13 Synthesis of various2-[2-(3-aminophenyl)ethyl]thiazoles

By carrying out the treatment similarly as in Synthesis example 12,various 2-[2-(3-aminophenyl)ethyl]thiazoles shown as Nos. 34 and 35 inTable 1 were obtained.

SYNTHESIS EXAMPLE 14 Synthesis of 2-(trans-3-amino-4-hydroxystyryl)benzothiazole

To a solution of 282 mg of2-(trans-3-amino-4-methoxystyryl)benzothiazole dissolved in 30 ml ofdichloromethane was added 380 mg of phosphorous tribromide at 70° C.,and the mixture was gradually returned to room temperature and stirredovernight. After an aqueous saturated sodium hydrogen carbonate solutionwas added to the reaction mixture to make it weakly alkaline, themixture was extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure to give 260 mg (yield 97%) of the title compound.

m.p.: 192°-193° C.

IR: ν=3400, 1590, 1510, 1290, 800, 760 cm⁻¹.

SYNTHESIS EXAMPLE 15 Synthesis of 2-(trans-3-amino-6-hydroxystyryl)benzothiazole

By carrying out the treatment similarly as in Synthesis example 14, thetitle compound shown as No. 33 in Table 1 was obtained.

SYNTHESIS EXAMPLE 16 Synthesis of2-(trans-3-aminostyryl)-5-methoxycarbonylbenzothiazole

To a solvent mixture of 50 ml of dioxane and 30 ml of methanol, 2.0 g of5-methoxycarbonyl-2-(trans-3-nitrostyryl)benzothiazole was added and,under vigorous stirring, a solution of 0.37 g of calcium chloride in 55ml of water and 9.8 g of zinc powder were added, followed by refluxingfor 2 hours. After cooled to room temperature, the reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure, andthe solid residue formed was washed with toluene to give 1.4 g (yield77%) of the title compound.

m.p.: 165°-167° C.

IR: ν=1710, 1630, 1305, 1100, 755 cm⁻¹.

EXAMPLE 1 Synthesis of 2-[trans-3-(cis-3-carboxypropenamide)styryl]benzothiazole (compound No. 1)

To 8 ml of toluene were added 158 mg of2-(trans-3-aminostyryl)benzothiazole and 71 mg of maleic anhydride, andthe mixture was heated at 80° C. for 1 hour. After cooled to roomtemperature, the crystals formed were collected by filtration andrecrystallized from ethanol to give 194 mg (yield 88%) of the yellowishwhite title compound.

m.p.: 190°-191° C.

IR: ν=1700, 1625, 1550, 1490, 1405, 953 cm⁻¹.

EXAMPLE 2 Synthesis of various anilide carboxylic acids

By carrying out the treatment similarly as in Example 1, the titlecompounds shown as compounds Nos. 2-165 and 445-448 in Table 2 wereobtained.

EXAMPLE 3 Synthesis of 2-(trans-3-oxalylaminostyryl)-4-phenylthiazole(compound No. 166)

To a suspension of 1.0 g of2-(trans-3ethyloxalylaminostyryl)-4-phenylthiazole in 40 ml of dioxanewas added, under vigorous stirring, 1 ml of an aqueous 20% potassiumhydroxide solution, and hydrolysis was carried out at room temperaturefor 1 hour. To the reaction mixture was added 20% hydrochloric acid toadjust the pH to 1-2, and the yellow precipitates formed were collectedby filtration and washed with ethanol and chloroform, followed by dryingunder reduced pressure to give 870 mg (yield 94%) of the title compound.

m.p.: 291°-292° C.

IR: ν=1715, 1685, 1590, 1520, 1300, 1180, 740 cm⁻¹.

EXAMPLE 4 Synthesis of various anilidecarboxylic acids

By carrying out the treatment similarly as in Example 3, the titlecompounds shown as compounds Nos. 167-169 in Table 2 were obtained.

EXAMPLE 5 Synthesis of 2-[trans-3-(3-carboxypropylamino)styryl]-4-propylthiazole (compound No. 170)

To 20 ml of toluene were added 732 mg of2-(trans-3-aminostyryl)-4-propylthiazole, 1170 mg of ethyl4-bromobutyrate and 606 mg of triethylamine, and the reaction wascarried out at 100° C. for 21 hours. After the reaction mixture wascooled to room temperature, 10 ml of ethanol and 10 ml of an aqueous 5%sodium hydroxide solution were added and the mixture was stirred at roomtemperature for 1.5 hours to effect hydrolysis of the ester. Aftercompletion of the reaction, ethanol was evaporated under reducedpressure and the residue was adjusted to pH 1-2 with addition of 10%hydrochloric acid, followed by extraction with ethyl ether. After dryingover anhydrous magnesium sulfate, the solvent was evaporated and thesolid formed was recrystallized from ethyl ether to give 629 mg (yield64%) of the title compound.

m.p.: 115°-116° C.

IR: ν=1705, 1595, 1480, 1190, 940, 740 cm⁻¹.

EXAMPLE 6 Synthesis of various anilinocarboxylic acid

By carrying out the treatment similarly as in Example 5, the titlecompounds shown as compounds Nos. 171-182 in Table 2 were obtained.

EXAMPLE 7 Synthesis of2-(trans-3-ethyloxalylaminostyryl)-4-phenylthiazole (compound No. 183)

To 30 ml of toluene were added 0.7 g of pyridine and 2.0 g of2-(trans-3-aminostyryl)-4-phenylthiazole and a solution of 1.1 g ofethyloxalyl chloride in 5 ml of toluene was added dropwise at 0° C.under stirring, followed by heating at 50° C. for 1.5 hours. Thereaction mixture was poured into ice-cold water and crystals formed werecollected by filtration and dried, followed by recrystallization fromchloroform to give 2.5 g (yield 90%) of the title compound.

m.p.: 193°-194° C.

IR: ν=3325, 1715, 1700, 1300, 730 cm⁻¹.

EXAMPLE 8 Synthesis of various anilidecarboxylic acid esters

By carrying out the treatment similarly as in Example 7, the titlecompounds shown as compounds Nos. 184-188 in Table 2 were obtained.

EXAMPLE 9 Synthesis of2-[trans-3-(cis-3-isoamyloxycarbonylpropenamide)styryl]benzothiazole(compound No. 189)

To 6 ml of hexamethylphosphoric triamide were added 1.0 g of sodium saltof 2-[trans-3-(cis-3-carboxypropenamide)styryl]benzothiazole and 2.13 gof isoamyliodide, and the mixture was stirred at room temperature for 4hours. The reaction mixture was extracted with toluene in a conventionalmanner, the extract was dried over anhydrous magnesium sulfate and thesolvent was evaporated under reduced pressure, followed byrecrystallization of the residue from ethyl ether-toluene to give 616 mg(yield 55%) of the title compound.

m.p.: 82°-83° C.

IR: ν=3400, 1720, 1660, 1580, 1440, 1200, 755 cm⁻¹.

EXAMPLE 10 Synthesis of various anilidecarboxylic acid esters

By carrying out the treatment similarly as in Example 9, the titlecompounds shown as compounds Nos. 190-195 in Table 2 were obtained.

EXAMPLE 11 Synthesis of2-[trans-3-(4-ethoxycarbonyl)butylstyryl]benzothiazole (compound No.196)

A mixture of 460 mg of ethyl 5-(3-formylphenyl) pentanoate, 322 mg of2-methylbenzothiazole and 0.11 ml of acetic anhydride was heated undernitrogen gas stream to 170° C. for 30 hours. The reaction mixture wasdirectly purified through silica gel column chromatography by use ofethyl ether-n-hexane to obtain 320 mg (yield 45%) of the title compoundas brown oily product.

IR: ν=1720, 1620, 1485, 1180, 950, 750 cm⁻¹.

NMR (CCl₄): δ=1.25(3H,t), 1.35-2.05(4H,m), 2.01-2.85(4H,m), 4.07(2H,q),7.05-8.10(10H,m).

EXAMPLE 12 Synthesis of various2-(trans-3-alkoxycarbonylalkylenestyryl)benzothiazoles

By carrying out the treatment similarly as in Example 11, the titlecompounds shown as compounds Nos. 197 and 198 in Table 2 were obtained.

EXAMPLE 13 Synthesis of 2-[trans-3-(3-ethoxycarbonylpropyl)aminostyryl]benzothiazole (compound No. 199)

To 10 ml of toluene were added 1.0 g of2-(trans-3-aminostyryl)benzothiazole, 0.78 g of ethyl 4-bromobutyrateand 0.4 g of triethylamine, and the mixture was stirred at 100° C. for20 hours. After cooled to room temperature, the mixture was extractedwith toluene, dried over anhydrous magnesium sulfate and then thesolvent was evaporated under reduced pressure. The residue was purifiedthrough silica gel column chromatography by use of ethylacetate-n-hexane to obtain 951 mg of the title compound (yield 66%).

m.p.: 68°-69° C.

NMR (CDCl₃): δ=1.25(3H,t), 2.0(2H,m), 2.35(2H,t), 3.22(2H,t),4.23(2H,q), 6.45-8.10(10H,m).

EXAMPLE 14 Synthesis of various anilinocarboxylic acid esters

By carrying out the treatment similarly as in Example 13, the titlecompounds shown as compounds Nos. 200-205 in Table 2 were obtained.

EXAMPLE 15 Synthesis of2-(trans-3-ethoxycarbonylmethoxystyryl)benzothiazole (compound No. 206)

To 30 ml of acetone were added 200 mg of2-(trans-3-hydroxystyryl)benzothiazole, 0.11 ml of ethyl bromoacetateand 131 mg of potassium carbonate, and the mixture was refluxed for 4hours. After cooled to room temperature, the mixture was extracted withethyl ether, dried over anhydrous magnesium sulfate and then the solventwas evaporated under reduced pressure. After the crude crystals of theresidue were washed with ethyl ether and n-hexane, they were dried underreduced pressure to give 207 ml (yield 77%) of the title compound.

m.p.: 150°-151° C.

IR: ν=1720, 1585, 1260, 1190, 1025, 950, 755 cm⁻¹.

EXAMPLE 16 Synthesis of various alkoxycarbonylalkylphenylethers

By carrying out the treatment similarly as in Example 15, the titlecompounds shown as compounds Nos. 207-212 and 431-433 in Table 2 wereobtained.

EXAMPLE 17 Synthesis of 2-[trans-3-(cis-3-carboxypropenamide)styryl]benzothiazole sodium salt (compound No. 213)

To 350 ml of methanol was added 17.3 g of2-[trans-3-(cis-3-carboxypropenamide)styryl]benzothiazole and then asolution of 4.1 g of sodium hydrogen carbonate in 75 ml of water,followed by refluxing for 1 hour. The solvent was evaporated underreduced pressure, and the crude crystals of the residue were washed withethanol and ethyl ether, followed by drying under reduced pressure togive 18.9 g (yield: quantitative) of the title compound.

m.p.: 256°-258° C.

IR: ν=1650, 1625, 1560, 1490, 855, 750 cm⁻¹.

EXAMPLE 18 Synthesis of sodium salts of various carboxylic acids havingthiazole groups

By carrying out the treatment similarly as in Example 17, the titlecompounds shown as compounds Nos. 214-395 and 434-436 in Table 2 wereobtained.

EXAMPLE 19 Synthesis of2-[trans-3-(3-carboxypropyl)aminostyryl]benzothiazole sodium salt(compound No. 396)

To 8 ml of ethanol were added 1.16 g of2-[trans-3-(3-ethoxycarbonylpropyl)aminostyryl]benzothiazole and 5 ml of5% aqueous sodium hydroxide solution, and the mixture was stirred at 60°C. for 1.5 hours. After evaporation of the solvent together with tolueneunder reduced pressure, the residue was diluted with ethanol and heatedto 50° C. After cooled to room temperature, the crystals formed werecollected by filtration and washed with ethanol-ethyl ether, followed bydrying under reduced pressure to give 1.11 g (yield 97%) of the titlecompound.

m.p.: 239°-240° C.

IR: ν=1360, 1570, 1410, 940, 760 cm⁻¹.

EXAMPLE 20 Synthesis of sodium salts of various carboxylic acids havingthiazole groups

By carrying out the treatment similarly as in Example 19, the titlecompound shown as compounds Nos. 397-413 in Table 2 were obtained.

EXAMPLE 21 Synthesis of2-[trans-3-(cis-2-carboxycyclohexanoyl)aminostyryl]benzothiazoleN-methyl-D-glucamine salt (compound No. 414)

Into a solvent mixture of 6 ml of methanol and 1 ml of water were added96 mg of N-methyl-D-glucamine and 200 mg of2-[trans-3-(cis-2-carboxycyclohexanoyl)aminostyryl]benzothiazole and themixture was stirred at room temperature for 30 minutes. Afterevaporation of the solvent under reduced pressure, the crude crystalsformed were recrystallized from ethanol-ethyl ether to obtain 215 mg(yield 73%) of the title compound.

m.p.: 113°-115° C., 245°-246° C.

IR: ν=1680, 1540, 1410, 1080, 750 cm⁻¹.

EXAMPLE 22 Synthesis of salts with organic bases of various carboxylicacids having thiazole groups

By carrying out the treatment similarly as in Example 21, the titlecompounds shown as compounds Nos. 415-421 in Table 2 were obtained. InTable 2, the following abbreviations were used.

NMG: N-methyl-D-glucamine,

Tris: tris(hydroxymethyl)aminomethane.

EXAMPLE 23 Synthesis of 2-[trans-3-(4-hydroxybutanoylamino)styryl]benzothiazole (compound No. 422)

A solution of 1.0 g of 2-(trans-3-aminostyryl)benzothiazole dissolved in15 ml of anhydrous tetrahydrofuran was cooled to -78° C. and 2.8 ml of an-hexane solution (1.55M) of n-butyl lithium was added dropwise in anitrogen gas atmosphere. After a mixture was stirred at the sametemperature for 25 minutes, 375 mg of γ-butyrolactone was injected,followed by stirring for 1 hour. After completion of the reaction, themixture was extracted with ethyl acetate, dried over magnesium sulfateand the solvent was evaporated under reduced pressure. The crudecrystals obtained were washed with ethyl ether and dried to obtain 160mg (yield 12%) of the title compound.

m.p.: 191°-192° C.

IR: ν=3400, 1640, 1580, 1530, 1420, 1050, 940, 755 cm⁻¹.

EXAMPLE 24 Synthesis of 2-[trans-3-(4-hydroxybutoxy)styryl]benzothiazole(compound No. 423)

To 40 ml of ethyl ether was added 1.0 g of2-[trans-3-(3-ethoxycarbonylpropoxy)styryl]benzothiazole, and 114 mg oflithium aluminum hydride was added under ice-cooling. After the mixturewas stirred at the same temperature for 30 minutes, then at roomtemperature for 40 minutes, 114 μl of water, 114 μl of 15% aqueoussodium hydroxide and 340 μl of water were successively added slowly todecompose the aluminum complex, followed by extraction with toluene.After drying over anhydrous magnesium sklfate, the solvent wasevaporated under reduced pressure and the crude crystals formed werewashed with ethyl ether under ice-cooling, followed by drying underreduced pressure to give 570 mg (yield 64%) of the title compound.

m.p.: 88°-90° C.

IR: ν=3280, 1590, 1570, 1285, 950, 760 cm⁻¹.

EXAMPLE 25 Synthesis of2-[trans-3-(3-(5-tetrazolyl)propylamino)styryl]benzothiazole (compoundNo. 424)

To 5 ml of dimethylformamide were added 390 mg of sodium azide and 638mg of 2-[trans-3-(3-cyanopropylamino)styryl]benzothiazole, and themixture was heated to 120° C. for 7 hours. After cooled to roomtemperature, the mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate and the solvent was evaporation underreduced pressure. The concentrate was purified through silica gel columnchromatography by use of ethyl acetate to obtain 250 mg (yield 35%) ofthe title compound.

m.p.: 168°-169° C.

IR: ν=1625, 1595, 1460, 1430, 950, 760 cm⁻¹.

EXAMPLE 26 Synthesis of2-[trans-3-(2-carboxyanilino)styryl]benzothiazole (compound No. 425)

To 10 ml of isoamyl alcohol were added 504 mg of2-(trans-3-aminostyryl)benzothiazole, 311 mg of 2-chlorobenzoic acid,290 mg of potassium carbonate, 1 mg of iodine and 15 mg of copperpowder, and the mixture was refluxed for 6 hours. The solvent wasevaporated under reduced pressure and the residue was extracted withethyl acetate. The crude product after evaporation of the solvent waspurified through silica gel column chromatography by use of ethylacetate-toluene to obtain 83 mg (yield 11%) of the title compound.

IR: ν=1630, 1570, 1380, 1285, 1200, 750 cm⁻¹.

m.p.: 146°-150° C.

EXAMPLE 27 Synthesis of 2-[trans-3-(2-carboxyethylamino)styryl]benzothiazole sodium salt (compound No. 426)

To 1 ml of acetonitrile were added 1.0 g of2-(trans-3-aminostyryl)benzothiazole and 1 ml of β-propiolactone, andthe mixture was refluxed for 1 hour. After evaporation of acetonitrileunder reduced pressure, toluene and 10% hydrochloric acid were added tothe residue. After the insolubles were filtered off, the filtrate wasmade alkaline with addition of 10% aqueous sodium hydroxide solution andthe precipitates formed were collected by filtration. The crude productwas recrystallized from methanol-ethyl acetate to obtain 224 mg (yield16%) of the title compound.

m.p.: 250° C. (decomposed)

IR: ν=1565, 1405, 1005, 940, 750 cm⁻¹.

EXAMPLE 28 Synthesis of2-[3-(2-carboxyethylamino)styryl]-4,5-dimethylthiazole sodium salt(compound No. 427)

An amount of 230 mg of 2-(trans-3-aminostyryl)-4,5-dimethylthiazole, 1ml of methyl acrylate and two drops of acetic acid were added to 1.5 mlof toluene and the mixture was refluxed for 16 hours. The mixture wasextracted in a conventional manner with ethyl acetate, the solvent wasevaporated under reduced pressure and the residue was purified throughsilica gel column chromatography by use of ethyl acetate-n-hexane toobtain 160 mg of acrylate adduct. Next, 160 mg of the ester wasdissolved in 5 ml of ethanol, and 2 ml of 5% aqueous sodium hydroxidewas added to carry out hydrolysis by stirring at room temperature for 1hour. The precipitates formed were collected by filtration, washed withwater and then with ethyl ether, followed by drying under reducedpressure to obtain 90 mg (yield 28%) of the title compound.

m.p.: 120°-123° C.

IR: ν=1595, 1550, 1405, 945, 765 cm⁻¹.

EXAMPLE 29 Synthesis of 2-[trans-3-(2-carboxyethylamino)styryl]-4-phenylthiazole sodium salt (compound No. 428)

By carrying out the treatment similarly as in Example 28, 93 mg (yield23%) of the title compound was obtained.

m.p.: 261°-263° C. (decomposed).

IR: ν=1700, 1590, 1440, 1220, 1195, 760 cm⁻¹.

EXAMPLE 30 Synthesis of 2-[trans-3-(2-carboxyethoxy)styryl]benzothiazole(compound No. 429)

To 3 ml of dimethylformamide were added 47 mg of 60% sodium hydride and300 mg of 2-(trans-3-hydroxystyryl)benzothiazole, and the mixture wasstirred at room temperature for 30 minutes. Then, 74 μl ofβ-propiolactone was added and the mixture was further stirred for 4.5hours. The acidic portion was extracted in a conventional manner withchloroform, and after drying over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure and the crude crystalswere washed with ethyl ether, followed by drying under reduced pressureto give 118 mg (yield 31%) of the title compound.

m.p.: 177°-178° C.

IR: ν=1705, 1590, 1440, 1215, 1195, 960, 760 cm⁻¹.

EXAMPLE 31 Synthesis of2-[trans-3-(3-carboxy-3,3-dimethylpropyloxy)styryl]-4-isopropylthiazole(compound No. 430)

To a solution of 200 mg of2-[trans-3-(3,3-dimethyl-3-ethoxycarbonylpropyloxy)styryl]-4-isopropylthiazoledissolved in 5 ml of ethanol were added 2 ml of 10% aqueous potassiumhydroxide solution and three drops of 40% benzyltrimethylammoniumhydroxide methanol solution, and the mixture was refluxed for 1 hour toeffect hydrolysis of the ester. After completion of the reaction,ethanol was evaporated under reduced pressure and the residue wasadjusted to pH 1-2 with addition of 10% hydrochloric acid and thenextracted with ethyl ether. After drying of anhydrous magnesium sulfate,the solvent was evaporated and the solid formed was recrystallized frommethanol to give 123 mg (yield 66%) of the title compound.

m.p.: 112°-113° C.

IR: ν=1705, 1285, 1160, 1100, 740 cm⁻¹.

EXAMPLE 32 Synthesis of various styrylcarboxylic acids

By carrying out the treatment similarly as in Example 31, the titlecompounds shown as compounds Nos. 438-444 in Table 2 were obtained.

EXAMPLE 33 Preparation of tablets

An amount of 1000 g of well pulverized2-[trans-3-(cis-3-carboxypropenamide)styryl]benzothiazole sodium salt(compound No. 213), 5900 g of lactose, 2000 g crystalline cellulose,1000 g of a low substitution degree hydroxypropyl cellulose and 100 g ofmagnesium stearate were well mixed and formed into plain tablesaccording to the direct tableting method containing 10 mg of the abovecompound in 100 mg of one tablet. The plain tablet was applied withsugar coating or film coating to prepare sugar-coated tablet andfilm-coated tablet.

EXAMPLE 34 Preparation of capsules

An amount of 1000 g of well pulverized2-[trans-3-(cis-3-carboxypropenamide)styryl]benzothiazole sodium salt(compound No. 213), 3000 g of corn starch, 6900 g of lactose, 1000 g ofcrystalline cellulose and 100 g of magnesium stearate were mixed toprepare capsules containing 10 mg of the above compound in 120 mg of onecapsule.

EXAMPLE 35 Preparation of inhalent

An amount of 5 g of well pulverized2-[trans-3-(cis-3-carboxypropenamide)styryl]benzothiazole sodium salt(compound No. 213), 10 g of a middle chain saturated fatty acidtriglyceride and 0.2 g of sorbitane monooleate were well mixed, and each15.2 mg of the mixture was weighed in 5 ml of an aluminum vessel foraerosol. Further, after 84.8 mg of Freon 12/114 (1:1 mixture) was filledper one vessel at low temperature, the vessel was equipped with aquantitative adaptor of 100 μl per 1 spray to prepare an inhalent ofquantitative spray containing 5 mg of the above compound in 5 ml of onevessel.

EXAMPLE 36 SRS antagonistic action in vitro

The ileum end portion of a male Hartley-strain guinea pig weighing200-450 g was extirpated and after washing its lumen, the ileum wasmounted within 5 ml of a tissue bath containing a Tylord solutioncomprising the following components. The components are 136 mM NaCl, 2.7mM KCl, 11.9 mM NaHCO₃, 1.05 mM MgCl₂, 1.8 mM CaCl₂, 0.4 mM NaH₂ PO₄ and5.6 mM glucose. The liquid temperature in the bath was maintained at 37°C., and aeration was effected with 95% oxygen/5% carbon dioxide. Forremoving shrinkage with hystamine and acetylcholine, 10⁻⁷ g/ml ofmepylamin and 5×10⁻⁸ g/ml of atropin were added to the above buffer.Isotonic measurement was conducted by isotonic transducer (TD-112S,trade name, produced by Nippon Koden) tension replacement convertor andrecorded by Recticoder (RTG-4124, trade name, produced by Nippon Koden)as the change in grams of tension. The ileum was loaded passively with0.5 g of tension and the ileum shrinkage reaction to SRS extracted fromguinea pig lung was obtained. The persistent shrinkage height by oneunit of SRS (corresponding to 5 ng of hystamine) was used as control.Test drugs of various concentrations were added into the tissue bath,and the results of minimum effective concentration which is theconcentration of the test drug attenuating shrinkage of control to 50%(IC₅₀) are shown in Table 2 and Table 3.

EXAMPLE 37 LTD₄ antagonistic action in vivo

For male Hartley-strain guinea pig weighing 350-500 g under urethaneanesthesia, airway resistance was measured by use of a Harvard typerespirator according to the method which is a modification of theKonzett-Roessler method, inhibition (%) by intraduodenal administrationof the test drug against airway resistance increase by intraveneousadministration of 0.1-1.0 μg/kg of LTD₄ was calculated to obtain theresults shown in Table 2 and Table 4.

TEST EXAMPLE Acute toxicity test

With 4 to 5 ddy-strain male mice of 6 weeks old as one group, thecompound of the present invention was orally administered as asuspension in 1% tragacanth solution, and observation was conducted for7 days and the number of dead mice was examined to obtain the resultsshown in Table 5.

                  TABLE 1-1                                                       ______________________________________                                         ##STR32##                    (IIa)                                           No.     R.sub.1       R.sub.2    m.p. (°C.)                            ______________________________________                                        1       Me            Me         148˜149                                2       Et            "          76˜77                                  3       "             H          60˜61                                  4       CH.sub.3 (CH.sub.2).sub.2                                                                   "          61˜62                                  5       CH.sub.3 (CH.sub.2).sub.3                                                                   "          79˜80                                  6       CH.sub.3 (CH.sub.2).sub.4                                                                   "          56˜57                                  7       CH.sub.3 (CH.sub.2).sub.5                                                                   "          65˜66                                  8       CH.sub.3 (CH.sub.2).sub.6                                                                   "          56˜57                                  9       CH.sub.3 (CH.sub.2).sub.7                                                                   "          50˜51                                  10      CH.sub.3 (CH.sub.2).sub.2                                                                   Et         58˜59                                  11      (CH.sub.3).sub.3 C                                                                          H          74˜75                                  12      Me            CH.sub.3 (CH.sub.2).sub.3                                                                58˜59                                  13      C.sub.6 H.sub.5                                                                             "          138˜139                                14       COOEt        H          93˜94                                  15      (CH.sub.2).sub.4     156˜157                                    16      C.sub.6 H.sub.5                                                                             H          137˜139                                17      p-Cl C.sub.6 H.sub.4                                                                        "          177˜178                                18      m-MeC.sub.6 H.sub.4                                                                         "          117˜118                                19      p-EtOOCC.sub.6 H.sub.4                                                                      "          145˜146                                20      p-MeC.sub.6 H.sub.4                                                                         "          156˜157                                21      p-MeOC.sub.6 H.sub.4                                                                        "          141˜142                                ______________________________________                                    

                  TABLE 1-2                                                       ______________________________________                                         ##STR33##                    (IIb)                                           No.    X             Y       m.p. (°C.)                                ______________________________________                                        22     H             H       178˜179                                    23     5-OMe         "       143˜144                                    24     5-Me          "       150˜151                                    25     5-Cl          "       168˜169                                    26     6-OMe         "       158˜160                                    27     H             2-Me    118˜120                                    28     "             6-OMe   147˜148                                    29     "             4-Cl    174˜176                                    30     "             6-Cl    191˜192                                    31     "             2-OH    180˜181                                    32     "             4-OMe   155˜156                                    33     "             6-OH    234˜236                                    ______________________________________                                    

                  TABLE 1-3                                                       ______________________________________                                         ##STR34##                    (IIc)                                           No.   R.sub.1    R.sub.2 A         m.p. (°C.)                          ______________________________________                                        34                                                                                   ##STR35##     (CH.sub.2).sub.2                                                                          79˜80                                  35    (CH.sub.3).sub.2 CH                                                                      H       "         --*                                        36    H          "       CH.sub.2 OCH.sub.2                                                                      --**                                       37    "          "       OCH.sub.2 120˜121                              38    "          "       NHCH.sub.2                                                                              102˜103                              ______________________________________                                         *IR: 1600, 1450, 1160, 1100, 770, 730                                         **IR: 1620, 1460, 1310, 1090, 865, 760                                   

                                      TABLE 2-1                                   __________________________________________________________________________     ##STR36##                                                                                                                        Anti-SRS                                                                            Airway                                                                  action                                                                              resistance          Com-                                                [minimum                                                                            increase            pound                       m.p.                    effective                                                                           inhibition          No. R.sub.14          X     (°C.)                                                                       Physical property values                                                                         conc.                                                                               (%)]                __________________________________________________________________________         ##STR37##        H     193˜4                                                                        IR 1700, 1670, 1580, 1541, 1260,                                                                 5 × 10.sup.-9       3                                                                                  ##STR38##        "     191˜2                                                                        IR 1705, 1660, 1542, 1488, 1080,                                                                 5 × 10.sup.-8       4                                                                                  ##STR39##        "     190˜3                                                                        IR 1705, 1660, 1600, 1540, 950, 760          5                                                                                  ##STR40##        "     236˜7                                                                        IR 1715, 1650, 1530, 1080, 950, 750          6   (CH.sub.2).sub.2 COOH                                                                           "     219˜20                                                                       IR 1690, 1540, 1315, 1210, 760               7   (CH.sub.2).sub.3 COOH                                                                           "     227˜30                                                                       IR 1705, 1640, 1530, 1415, 1080, 765         8                                                                                  ##STR41##        "     189˜90                                                                       IR 1690, 1670, 1410, 1200, 950, 750          9                                                                                  ##STR42##        "     198˜202                                                                      IR 1705, 1650, 1540, 1250, 780               10                                                                                 ##STR43##        "     168˜171                                                                      IR 1660, 1550, 1495, 1440, 1215, 955,                                         755                                          11                                                                                 ##STR44##        "     177˜8                                                                        IR 1710, 1670, 1545, 1200, 755               12                                                                                 ##STR45##        H     160˜1                                                                        IR 1680, 1540, 1200, 950, 750                13                                                                                 ##STR46##        "     191˜2                                                                        IR 1705, 1660, 1540, 1180, 755               14                                                                                 ##STR47##        "     169˜70                                                                       IR 1700, 1660, 1540, 1200, 950, 750          15                                                                                 ##STR48##        "     163˜4                                                                        IR 1710, 1660, 1540, 750                     16                                                                                 ##STR49##        "     140˜1                                                                        IR 1700, 1655, 1540, 1310, 950, 750          17                                                                                 ##STR50##        "     191˜2                                                                        IR 1680, 1540, 1417, 1190, 753               18                                                                                 ##STR51##        "     169˜70                                                                       IR 3210, 2950, 1680, 1540, 1080, 950,                                         750                                          19                                                                                 ##STR52##        5-Me  211˜2                                                                        IR 1695, 1620, 1550, 1400, 850, 785          20                                                                                 ##STR53##        "     207˜8                                                                        IR 1705, 1650, 1260, 940, 790, 690           21                                                                                 ##STR54##        "     184˜5                                                                        IR 1715, 1660, 1525, 1200, 945, 790          22  (CH.sub.2).sub.2 COOH                                                                           "     249˜50                                                                       IR 1710, 1650, 1580, 1180, 945, 800          23  (CH.sub.2).sub.3 COOH                                                                           "     236˜8                                                                        IR 1710, 1655, 1425, 1200, 955, 780          24                                                                                 ##STR55##        5-Cl  224˜5                                                                        IR 1695, 1550, 1400, 950, 855, 785           25                                                                                 ##STR56##        5-Cl  249˜50                                                                       IR 1700, 1580, 1230, 1065, 785               26                                                                                 ##STR57##        "     189˜90                                                                       IR 1700, 1520, 1350, 1200, 950, 800          27  (CH.sub.2).sub.2 COOH                                                                           "     244˜5                                                                        IR 1690, 1650, 1580, 1200, 940, 800          28  (CH.sub.2).sub.3 COOH                                                                           "     226˜7                                                                        IR 1705, 1660, 1540, 1200, 945, 800          29                                                                                 ##STR58##        5-OMe 199˜200                                                                      IR 1730, 1690, 1550, 1160, 850, 780          30                                                                                 ##STR59##        "     198˜9                                                                        IR 1710, 1580, 1235, 950, 780                31                                                                                 ##STR60##        "     >350 IR 1700, 1550, 1405, 1160, 1120, 950,                                         790                                          32  (CH.sub.2).sub.2 COOH                                                                           "     251˜2                                                                        IR 1700, 1650, 1180, 940, 680                33                                                                                 ##STR61##        6-OMe 208˜9                                                                        IR 1710, 1660, 1600, 1540, 1495, 1260,                                        1180, 830                                    167                                                                                ##STR62##        H     277˜80                                                                       NMR (CDCl.sub.3DMSOd.sub.6): δ=6.56                                     (2H,d), 6.83˜6.9(11H,                                                   m), 10.07(1H, s)   2 × 10.sup.-7       168 HOOC              "     213˜5                                                                        NMR (CDCl.sub.3DMSOd.sub.6): δ=                                         7.33˜8.30(11H, m), 10.73(1H, broad                                      s)                 10.sup.-7                 184                                                                                ##STR63##        "     180˜1.5                                                                      IR 1705, 1680, 1545, 1300, 760               185 EtOOC             "     150˜4                                                                        IR 1730, 1700, 1300, 1208, 770               186 EtOOCCH.sub.2     H     134˜7                                                                        IR 1740, 1650, 1580, 1140, 1150, 940,                                         750                                          190                                                                                ##STR64##        "     130˜1                                                                        IR 1685, 1615, 1580, 1210, 750               191                                                                                ##STR65##        "     132˜3                                                                        NMR (CDCl.sub.3): δ=1.82(6H,d),                                         1.27˜1.90(3H,m),4.18(2H,m),                                             6.82˜8.25(8H,m)                        192 MeOOC(CH.sub.2).sub.2                                                                           "     140˜1                                                                        IR 1735, 1680, 1580, 1550, 1420, 1155,                                        950, 760           5 × 10.sup.-7       193 EtOOC(CH.sub.2).sub.2                                                                           "     148˜50                                                                       IR 1720, 1680, 1540, 1175, 765               194                                                                                ##STR66##        "     149˜51                                                                       IR 1730, 1690, 1178, 953, 750                195                                                                                ##STR67##        "     82˜3                                                                         IR 1720, 1580, 1440, 1200, 755               214                                                                                ##STR68##        "     171˜3                                                                        IR 1560, 1490, 1445, 1220, 950               215                                                                                ##STR69##        "     274˜7                                                                        IR 1640, 1600, 1580, 1560, 1380, 743         216                                                                                ##STR70##        "     255˜7                                                                        IR 1640, 1550, 1483, 1405,                                                                             850                 217                                                                                ##STR71##        "     150˜60                                                                       IR 1660, 1560, 1420, 1305, 750               218 NaOOC(CH.sub.2).sub.2                                                                           "     249˜50                                                                       IR 1665, 1580, 1415, 945, 755                219 NaOOC(CH.sub.2).sub.3                                                                           "     260˜2                                                                        IR 1650, 1550, 1410, 940, 750                220                                                                                ##STR72##        "     180˜3                                                                        IR 1705, 1560, 1405, 1310, 760               221                                                                                ##STR73##        H     197˜202                                                                      IR 1625, 1560, 1400, 950, 760                222                                                                                ##STR74##        "     150˜5                                                                        IR 1655, 1540, 945, 870, 750                 223                                                                                ##STR75##        "     168˜71                                                                       IR 1660, 1550, 1495, 1440, 1215, 955,                                         755                                          224                                                                                ##STR76##        "     120˜5                                                                        IR 1650, 1540, 1210, 940,                                                                              890                 225                                                                                ##STR77##        "     125˜30                                                                       IR 1635, 1540, 1365, 925, 730                226                                                                                ##STR78##        "     125˜30                                                                       IR 1650, 1545, 1400, 950, 750                227                                                                                ##STR79##        "     180˜3                                                                        IR 1665, 1550, 950, 750                                                                          5 × 10.sup.-8       228                                                                                ##STR80##        "     200˜1                                                                        IR 2910, 1655, 1545, 1305, 750               229                                                                                ##STR81##        "     145˜50                                                                       IR 1650, 1540, 1210, 950, 750                230                                                                                ##STR82##        5-Me  225˜9                                                                        IR 1680, 1590, 1440, 1305, 950, 790          231                                                                                ##STR83##        "     273˜5                                                                        IR 1660, 1580, 1550, 945                                                                         5 × 10.sup.-9       232                                                                                ##STR84##        "     290˜303                                                                      IR 1680, 1590, 1530, 1400, 1300, 950,                                         785                      83                  233 NaOOC(CH.sub.2).sub.2                                                                           "     228˜31                                                                       IR 1660, 1565, 1410, 950, 790                234 NaOOC(CH.sub.2).sub.3                                                                           5-Me  213˜5                                                                        IR 1655, 1570, 1535, 1410, 1200              235                                                                                ##STR85##        5-COOMe                                                                             330˜5                                                                        IR 1700, 1585, 1540, 1400, 1300, 760         236                                                                                ##STR86##        5-Cl  257˜60                                                                       IR 1630, 1580, 1490, 1430, 955               237                                                                                ##STR87##        "     293˜6                                                                        IR 1680, 1590, 1565, 1490, 1390              238                                                                                ##STR88##        "     284˜94                                                                       IR 1680, 1580, 1530, 1400, 950, 790          239 NaOOC(CH.sub.2).sub.2                                                                           "     230˜4                                                                        IR 1655, 1580, 1540, 1430, 940               240 NaOOC(CH.sub.2).sub.3                                                                           "     215˜7                                                                        IR 1650, 1570, 1540, 1430, 940               241                                                                                ##STR89##        5-OMe 215˜7                                                                        IR 1630, 1585, 1430, 1280, 950, 800          242                                                                                ##STR90##        "     295˜8                                                                        IR 1675, 1590, 1540, 1490, 1390              243                                                                                ##STR91##        "     >350 IR 1560, 1400, 1270, 1190, 800               244 NaOOC(CH.sub.2).sub.2                                                                           "     241˜3                                                                        IR 1655, 1550, 1420, 950, 725                245                                                                                ##STR92##        6-OMe 260˜5                                                                        IR 1680, 1585, 1400, 1260, 950, 800          415                                                                                ##STR93##        H     179˜80                                                                       IR 1625, 1560, 1350, 1330, 1060, 750         416                                                                                ##STR94##        "     108˜9                                                                        IR 1625, 1615, 1550, 1380, 1050, 750         417                                                                                ##STR95##        "     135˜40 224˜5                                                           IR 1650, 1550, 1475, 1080, 755               418                                                                                ##STR96##        "     95˜6 (decompo- sition)                                                       IR 1660, 1550, 1400, 1080, 750               419 HOOC(CH.sub.2).sub.2.Tris                                                                       "     162˜3                                                                        IR 1630, 1605, 1600, 1580, 1410, 1060,                                        750                                          445                                                                                ##STR97##        "     133˜5                                                                        IR 1695, 1630, 1520, 1190,                   __________________________________________________________________________                                     750                                      

                                      TABLE 2-2                                   __________________________________________________________________________     ##STR98##                                                                                                                        Anti-SRS                                                                            Airway                                                                  action                                                                              resistance          Com-                                                [minimum                                                                            increase            pound                    m.p.                       effective                                                                           inhibition          No. R.sub.14       X     (°C.)                                                                         Physical property values                                                                          conc.                                                                               (%)]                __________________________________________________________________________    34                                                                                 ##STR99##     H     199˜200                                                                        1740, 1720, 1700, 1620, 1540, 1400, 845,                                      725                 2 × 10.sup.-8       35                                                                                 ##STR100##    "     201˜5                                                                          1720, 1620, 1575, 1550, 1242, 735             36                                                                                 ##STR101##    "     205˜6                                                                          1695, 1680, 1540, 1440, 1280, 945, 750        37                                                                                 ##STR102##    "     204˜5                                                                          1690, 1540, 1410, 1200, 940, 755              38  (CH.sub.2).sub.2 COOH                                                                        "     237˜8                                                                          1690, 1650, 1530, 1405, 735                   39  (CH.sub.2).sub.3 COOH                                                                        "     190˜2                                                                          1700, 1650, 1595, 1400, 950, 725              40                                                                                 ##STR103##    "     159˜60                                                                         3300, 2950, 1700, 1545, 1190, 950, 725        41                                                                                 ##STR104##    "     202˜3                                                                          1700, 1542, 1195, 945, 755                    42                                                                                 ##STR105##    "     184˜5                                                                          1685, 1660, 1600, 1328, 950, 730              43                                                                                 ##STR106##    "     182˜4                                                                          1660, 1550, 1490, 1440, 1210, 955, 755        44                                                                                 ##STR107##    p-Cl  204˜7                                                                          1695, 1615, 1530, 1395, 1080, 945, 840,                                       735                                           45                                                                                 ##STR108##    "     218˜20                                                                         1720, 1640, 1620, 1610, 1500, 1245, 780,                                      760                                           46                                                                                 ##STR109##    "     214˜5                                                                          1680, 1580, 1470, 1400, 940, 825, 770         47                                                                                 ##STR110##    "     210˜3                                                                          1685, 1580, 1540, 1200, 940, 770              48  (CH.sub.2).sub.3 COOH                                                                        "     179˜81                                                                         1685, 1655, 1595, 1530, 1400, 950, 740        49                                                                                 ##STR111##    p-Me  203˜4                                                                          1692, 1540, 1180, 950, 775                    50                                                                                 ##STR112##    "     202˜3                                                                          1690, 1540, 1200, 945, 775                    51                                                                                 ##STR113##    m-Me  197˜8                                                                          1690, 1540, 1180, 940, 770                    52                                                                                 ##STR114##    p-CMe 187˜8                                                                          1685, 1530, 1250, 1175, 770                   53                                                                                 ##STR115##    p-COOEt                                                                             204˜5                                                                          1705, 1545, 1415, 1280                        246                                                                                ##STR116##    H     225˜8                                                                          1650, 1560, 1440, 950, 735                    247                                                                                ##STR117##    "     266˜70                                                                         1660, 1580, 1550, 1400, 1380, 950, 730        248                                                                                ##STR118##    "     234˜5                                                                          1642, 1540, 1400, 955, 735                                                                              85                  249                                                                                ##STR119##    H     149˜50                                                                         1650, 1540, 1400, 955, 720                    250 NaOOC(CH.sub.2).sub.2                                                                        "     295˜8                                                                          1645, 1555, 1430, 1410, 815, 735              251 NaOOC(CH.sub.2).sub.3                                                                        "     275˜7                                                                          1660, 1600, 1540, 1400, 955, 730              252                                                                                ##STR120##    "     170˜4 (decompo- sition)                                                        1665, 1550, 1405, 950, 730                    253                                                                                ##STR121##    "     150˜2 (decompo- sition)                                                        1650, 1580, 1480, 1400,                                                                           5 × 10.sup.-8       254                                                                                ##STR122##    "     136˜9                                                                          1660, 1550, 1490, 1440, 1210, 955, 755        255                                                                                ##STR123##    p-Cl  225˜8                                                                          1560, 1470, 1085, 945, 735                    256                                                                                ##STR124##    "     307˜20                                                                         1680, 1610, 1590, 1530, 1385, 705             257                                                                                ##STR125##    "     273˜5                                                                          1660, 1550, 1465, 1080, 945, 825, 740         258                                                                                ##STR126##    "     159˜62                                                                         1660, 1560, 1470, 1400, 1085, 740             259 NaOOC(CH.sub.2).sub.3                                                                        "     288˜91                                                                         1660, 1600, 1550, 1400, 1095, 955, 745        260                                                                                ##STR127##    p-Me  255˜6                                                                          1665, 1560, 1480, 1405, 950, 740              261                                                                                ##STR128##    "     152˜3                                                                          1660, 1550, 1480, 1405, 950, 740              262                                                                                ##STR129##    m-Me  170˜80                                                                         1660, 1540, 1400, 950, 780, 730               263 "              p-CMe <280   1685, 1590, 1480, 1240, 745                   264 "              p-COOMe                                                                             <340   1690, 1590, 1540, 1400, 1290,                 __________________________________________________________________________                                    740                                       

                                      TABLE 2-3                                   __________________________________________________________________________     ##STR130##                                                                                                                       Anti-SRS                                                                            Airway                                                                  action                                                                              resistance          Com-                                                [minimum                                                                            increase            pound                    m.p.                       effective                                                                           inhibition          No. R.sub.14      R.sub.1                                                                              (°C.)                                                                          Physical property values                                                                         conc.                                                                               (%)]                __________________________________________________________________________    54                                                                                 ##STR131##   Me     157˜8                                                                           1700, 1620, 1550, 965,                                                                           5 × 10.sup.-7       55  (CH.sub.2).sub.2 COOH                                                                       "      199˜200                                                                         1720, 1640, 1530, 1080, 945                  56  (CH.sub.2).sub.3 COOH                                                                       "      208˜10                                                                          1705, 1645, 1525, 1080, 950                  57                                                                                 ##STR132##   Et     149˜50                                                                          1690, 1620, 1530, 850                        58                                                                                 ##STR133##   "      181˜3                                                                           1720, 1580, 1550, 1245, 780                  59                                                                                 ##STR134##   "      192˜3                                                                           1690, 1655, 1540, 1200, 790                  60  (CH.sub.2).sub.2 COOH                                                                       "      191˜2                                                                           1690, 1540, 1320, 1190, 780                  61  (CH.sub.2).sub.3 COOH                                                                       "      146˜7                                                                           1705, 1643, 1530, 1180, 950, 780             62                                                                                 ##STR135##   CH.sub.3 (CH.sub.2).sub.2                                                            151˜2                                                                           1700, 1620, 1550, 1410, 860                  63                                                                                 ##STR136##   "      180˜1                                                                           1720, 1625, 1580, 1245, 781                  64                                                                                 ##STR137##   CH.sub.3 (CH.sub.2).sub.2                                                            171˜2                                                                           1685, 1540, 1200, 785                        65  (CH.sub.2).sub.2 COOH                                                                       "      173˜4                                                                           1685, 1540, 1320, 1190, 950, 775             66  (CH.sub.2).sub.3 COOH                                                                       "      130˜1                                                                           1715, 1640, 1440, 1185, 950, 775             67                                                                                 ##STR138##   CH.sub.3 (CH.sub.2).sub.3                                                            151˜3                                                                           1695, 1615, 1545, 1400, 950, 855             68                                                                                 ##STR139##   "      168˜9                                                                           1715, 1650, 1575, 1480, 1240, 950, 780       69  (CH.sub.2).sub.2 COOH                                                                       "      149˜51                                                                          1700, 1680, 1540, 1480, 1320, 950, 755       70  (CH.sub.2).sub.3 COOH                                                                       "      81˜3                                                                            1680, 1650, 1600, 1555, 1485, 1135, 950                                       775                                          71                                                                                 ##STR140##   CH.sub.3 (CH.sub.2).sub.4                                                            143˜4                                                                           1700, 1550, 1410, 970, 860                   72                                                                                 ##STR141##   "      178˜9                                                                           1720, 1620, 1575, 1550, 1415, 1240, 960                                       775                                          73                                                                                 ##STR142##   "      161˜3                                                                           1690, 1540, 1440, 1410, 1200, 945            74                                                                                 ##STR143##   "      153˜5                                                                           1690, 1540, 1200, 945                        75  (CH.sub.2).sub.2 COOH                                                                       "      149˜51                                                                          1710, 1650, 1580, 1440, 1180, 945            76  (CH.sub.2).sub.3 COOH                                                                       "      87˜8                                                                            1680, 1658, 1605, 1340, 1200, 780            77                                                                                 ##STR144##   CH.sub.3 (CH.sub.2).sub.5                                                            142˜3                                                                           1700, 1620, 1555, 1535, 1405, 865            78                                                                                 ##STR145##   "      175˜6                                                                           1710, 1625, 1580, 1550, 1250                 79  (CH.sub.2).sub.2 COOH                                                                       "      145˜6                                                                           1720, 1660, 1585, 1530, 1440                 80  (CH.sub.2).sub.3 COOH                                                                       "      140˜1                                                                           1715, 1645, 1580, 1530                       81                                                                                 ##STR146##   CH.sub.3 (CH.sub.2).sub.8                                                            140˜1                                                                           1700, 1555, 1407, 860                        82                                                                                 ##STR147##   "      155˜7                                                                           1720, 1623, 1580, 1243, 965, 780             83  (CH.sub.2).sub.2 COOH                                                                       "      144˜5                                                                           1720, 1660, 1530, 1180, 960, 780             84  (CH.sub.2).sub.3 COOH                                                                       "      127˜8                                                                           1710, 1653, 1530, 785                        85                                                                                 ##STR148##   CH.sub.3 (CH.sub.2).sub.7                                                            160˜2                                                                           1685, 1540, 1200, 940                        86                                                                                 ##STR149##   (CH.sub.3).sub.3 C                                                                   185˜6                                                                           1700, 1550, 1405, 960, 860                   87                                                                                 ##STR150##   "      167˜8                                                                           1720, 1580, 1230, 955, 780                   88  (CH.sub.2).sub.2 COOCH                                                                      "      171˜2                                                                           1720, 1660, 1165, 960, 790                   89  (CH.sub.2).sub.3 COOCH                                                                      "      139˜40                                                                          1705, 1680, 1550, 1220, 960, 790             90                                                                                 ##STR151##   (CH.sub.3).sub.2 CH                                                                  148˜9                                                                           1695, 1615, 1540, 1300, 845                  91                                                                                 ##STR152##   "      118˜20                                                                          1690, 1620, 1525, 950                        92                                                                                 ##STR153##   "      182˜3                                                                           1720, 1580, 1240, 853, 778                   93                                                                                 ##STR154##   "      169˜70                                                                          1705, 1640, 1533, 1185, 955                  94  (CH.sub.2).sub.2 COOH                                                                       "      158˜9                                                                           1700, 1680, 1580, 1410, 955, 790, 740        95  (CH.sub.2).sub.3 COOH                                                                       "      143˜4                                                                           3270, 1710, 1640, 1440, 1180, 940            96                                                                                 ##STR155##   "      175˜6                                                                           1690, 1550, 1450, 960, 785                   97                                                                                 ##STR156##   "      175˜6                                                                           2950, 1710, 1650, 1180, 950, 755             98                                                                                 ##STR157##   "      160˜1                                                                           1707, 1640, 1543, 1170, 960, 783             99                                                                                 ##STR158##   "      199˜200                                                                         1705, 1660, 1540, 960, 695                   100                                                                                ##STR159##   "      155˜6                                                                           1705, 1655, 1540, 1170, 955, 780             101                                                                                ##STR160##   "      147˜8                                                                           1705, 1657, 1165, 955, 780                   102                                                                                ##STR161##   "      154˜5                                                                           1680, 1540, 1405, 1190, 950, 785             103                                                                                ##STR162##   "      175˜6                                                                           1680, 1540, 950, 790                         104                                                                                ##STR163##   (CH.sub.3).sub.2 CH                                                                  155˜6                                                                           3300, 2950, 1680, 1540, 950, 780             265                                                                                ##STR164##   Me     156˜7                                                                           1630, 1550, 1440, 940, 850, 765              266 "             Et     135˜40                                                                          1660, 1555, 1440, 950, 850, 780              267                                                                                ##STR165##   "      152˜5                                                                           1650, 1560, 1385, 955, 780                   268                                                                                ##STR166##   "      144˜6                                                                           1680, 1547 1405, 950, 780                    269 NaOOC(CH.sub.2).sub.2                                                                       "      165˜70                                                                          1660, 1555, 1410, 950, 785                   270 NaOOC(CH.sub.2).sub.3                                                                       "      210˜1                                                                           1645, 1550, 1410, 950, 785                   271                                                                                ##STR167##   (CH.sub.2).sub.2 CH.sub.3                                                            118˜20                                                                          1660, 1560, 1440, 950, 780                   272                                                                                ##STR168##   "      161˜3                                                                           1640, 1585, 1580, 950, 780                   273                                                                                ##STR169##   "      137˜40                                                                          1660, 1550, 1405, 950, 780                   274 NaOOC(CH.sub.2).sub.2                                                                       "      183˜5                                                                           1660, 1550, 1410, 1190, 950,                                                                     10.sup.31 7               275 NaOOC(CH.sub.2).sub.3                                                                       "      195˜7                                                                           1650, 1555, 1410, 950, 785                   276                                                                                ##STR170##   (CH.sub.2).sub.3 CH.sub.3                                                            123˜7                                                                           1695, 1615, 1545, 1400, 950, 855             277                                                                                ##STR171##   (CH.sub.2).sub.3 CH.sub.3                                                            120˜5                                                                           1650, 1600, 1580, 1560, 1385, 1325, 955.     278 NaOOC(CH.sub.2).sub.2        -                                                              "      185˜90                                                                          1665, 1560, 1410, 950, 785                   279 NaOOC(CH.sub.2).sub.3                                                                       "      187˜92                                                                          1650, 1580, 1555, 1435, 1410, 955            280                                                                                ##STR172##   (CH.sub.2).sub.4 CH.sub.3                                                            135˜8                                                                           1660, 1555, 1430, 948, 850                   281                                                                                ##STR173##   "      118˜20 (decompo- sition)                                                        1660, 1545, 1410, 955, 780                   282                                                                                ##STR174##   "      135˜40                                                                          1660, 1545, 1410, 950, 780                   283                                                                                ##STR175##   (CH.sub.2).sub.4 CH.sub.3                                                            95˜99                                                                           1660, 1560, 1410, 950, 780                   284 NaOOC(CH.sub. 2).sub.2                                                                      "      170˜6                                                                           1660, 1555, 1410, 945, 780                   285 NaOOC(CH.sub.2).sub.3                                                                       "      225˜6                                                                           1648, 1545, 1410, 948, 787                   286                                                                                ##STR176##   CH.sub.2).sub.5 CH.sub.3                                                             115˜7                                                                           1665, 1570, 1440, 955, 860                   287                                                                                ##STR177##   "      118˜20                                                                          1650, 1600, 1580, 1560, 1390,                                                                    2 × 10.sup.-5       288 NaOOC(CH.sub.2).sub.2                                                                       "      178˜80                                                                          1660, 1555, 1410, 950                        289 NaOOC(CH.sub.2).sub.3                                                                       "      167˜70                                                                          1650, 1550, 1410, 955                        290                                                                                ##STR178##   (CH.sub.2).sub.6 CH.sub.3                                                            125˜7                                                                           1660, 1560, 1440, 950, 850, 780              291                                                                                ##STR179##   "      114˜6                                                                           1650, 1580, 1390, 955,                                                                           10.sup.-7                 292 NaOOC(CH.sub.2).sub.2                                                                       "      150˜5                                                                           1660, 1558, 1410, 950, 785                   293 NaOCC(CH.sub.2).sub.3                                                                       "      199˜200                                                                         1650, 1555, 1415, 955, 790                   294                                                                                ##STR180##   (CH.sub.2).sub.7 CH.sub.3                                                            171˜3                                                                           1650, 1540, 1400, 950, 780                   295                                                                                ##STR181##   C(CH.sub.3).sub.3                                                                    154˜6                                                                           1660, 1560, 1440, 1350, 950, 780             296                                                                                ##STR182##   "      168˜71                                                                          1640, 1580, 1560, 1385, 955, 740             297 NaOOC(CH.sub.2).sub.2                                                                       "      174˜7                                                                           1660, 1600, 1560, 1415, 955                  298 NaOOC(CH.sub.2).sub.3                                                                       "      192˜3                                                                           1660, 1605, 1560, 1415,                                                                          5 × 10.sup.-5       299                                                                                ##STR183##   CH(CH.sub.3).sub.2                                                                   140˜5                                                                           1660, 1560, 1440, 1350, 950, 780             300                                                                                ##STR184##   "      145˜50                                                                          1650, 1600, 1555, 1380, 950, 740             301                                                                                ##STR185##   "      130˜2                                                                           1660, 1540, 1400, 955, 780                   302 NaOOC(CH.sub.2).sub.2                                                                       "      207˜10                                                                          1660, 1550, 1410, 945, 780                   303 NaOOC(CH.sub.2).sub.3                                                                       CH(CH.sub.3).sub.2                                                                   260˜70                                                                          1650, 1555, 1408, 943, 690                   304                                                                                ##STR186##   "      150˜3                                                                           1660, 1550, 1445, 1400, 1210, 955, 780       305                                                                                ##STR187##   "      120˜6                                                                           1660, 1550, 1410, 950, 780                   306                                                                                ##STR188##   "      100˜5                                                                           1650, 1540, 1400, 950, 780                   307                                                                                ##STR189##   "      127˜30                                                                          1660, 1575, 1380, 930,                                                                           2 × 10.sup.-9       308                                                                                ##STR190##   "      120˜5                                                                           1660, 1550, 1260, 960,                                                                                 965                 309                                                                                ##STR191##   "      55˜60                                                                           1650, 1550, 1400, 950, 780                   310                                                                                ##STR192##   "      130˜5                                                                           1650, 1540, 1400, 950,                                                                                 935                 311                                                                                ##STR193##   "      120˜3                                                                           1650, 1540, 1400, 950, 780                   312                                                                                ##STR194##   "      90˜95                                                                           1650, 1540, 1400, 950, 780                   446                                                                                ##STR195##   (CH.sub.2).sub.2 CH.sub.3                                                            159˜60                                                                          1670, 1520, 1190, 960, 760                   447                                                                                ##STR196##   "      155˜6                                                                           1670, 1540, 1410, 950, 780                   448                                                                                ##STR197##   "      164˜5                                                                           1680, 1580, 1410, 1200,                      __________________________________________________________________________                                     955                                      

                                      TABLE 2-4                                   __________________________________________________________________________     ##STR198##                                                                                                                       Anti-SRS                                                                            Airway                                                                  action                                                                              resistance          Com-                                                [minimum                                                                            increase            pound                       m.p.                    effective                                                                           inhibition          No. R.sub.14    R.sub.1, R.sub.2                                                                          (°C.)                                                                        Physical property values                                                                        conc.                                                                               (%)]                __________________________________________________________________________    105                                                                                ##STR199## Me, Me      150˜2                                                                         1705, 1620, 1580, 1540, 940, 840            106                                                                                ##STR200## "           181˜3                                                                         1700, 1650, 1545, 1255, 785                 107                                                                                ##STR201## "           175˜7                                                                         1660, 1600, 1545, 1210, 960, 780            108                                                                                ##STR202## "           195˜ 200                                                                      1705, 1655, 1605, 1545, 1180, 960, 780      109                                                                                ##STR203## "           197˜200                                                                       1680, 1580, 1540, 1430, 1215, 950, 780      110 (CH.sub.2).sub.2 COOH                                                                     "           203˜4                                                                         1710, 1660, 1600, 1550, 1230, 790           111 (CH.sub.2).sub.3 COOH                                                                     "           166˜9                                                                         1700, 1660, 1600, 1550, 1210, 945           112                                                                                ##STR204## "           206˜7                                                                         1675, 1540, 1405, 1200, 940, 785            113                                                                                ##STR205## "           167˜70                                                                        1650, 1540, 1440, 780                       114                                                                                ##STR206## "           199˜200                                                                       1680, 1540, 1200, 950, 780                  115                                                                                ##STR207## Et, Me      173˜4                                                                         1670, 1540, 1410, 1260, 955, 800            116                                                                                ##STR208## "           186˜7                                                                         1720, 1580, 1250, 950, 780                  117                                                                                ##STR209## "           186˜7                                                                         3320, 2910, 1690, 1540, 1410, 945, 780      118 (CH.sub.2).sub.2 COOH                                                                     "           215˜6                                                                         1680, 1540, 1300, 950, 780                  119 (CH.sub.2).sub.3 COOH                                                                     "           163˜4                                                                         3270, 1710, 1650, 1530, 1200, 780           120                                                                                ##STR210## "           178˜9                                                                         1700, 1660, 1540, 1210, 780                 121                                                                                ##STR211## "           200˜1                                                                         1703, 1650, 1540, 1250, 780                 122                                                                                ##STR212## "           211˜2                                                                         1680, 1540, 1410, 950, 785                  123                                                                                ##STR213## "           209˜10                                                                        1677, 1540, 1200, 950, 785                  124                                                                                ##STR214## "           184˜5                                                                         1700, 1655, 1600, 1540, 1175, 960, 785      125                                                                                ##STR215## CH.sub.3 (CH.sub.2).sub.2, Et                                                             144˜5                                                                         1720, 1600, 1550, 948, 845                  126                                                                                ##STR216## "           142˜3                                                                         1700, 1438, 1380, 1100, 710                 127                                                                                ##STR217## "           181˜3                                                                         1690, 1650, 1540, 1210, 950, 780            128 (CH.sub.2).sub.2 COOH                                                                     CH.sub.3 (CH.sub.2).sub.2, Et                                                             160˜1                                                                         1710, 1660, 1605, 1545, 960, 785            129 (CH.sub.2).sub.3 COOH                                                                     "           81˜2                                                                          1685, 1660, 1605, 1340, 1195, 780           130                                                                                ##STR218## C.sub.6 H.sub.5, (CH.sub.2).sub.3 CH.sub.3                                                204˜8                                                                         1720, 1620, 1580, 1545, 1235, 950, 780      131                                                                                ##STR219## "           133˜5                                                                         1680, 1580, 1530, 1410, 1200, 950, 785      132                                                                                ##STR220## Me,(CH.sub.2).sub.3 CH.sub.3                                                              173˜6                                                                         1720, 1620, 1580, 1545, 1240, 955, 780      133                                                                                ##STR221## "           164˜7                                                                         1700, 1655, 1600, 1540, 1080, 960, 780      134                                                                                ##STR222## (CH.sub.2).sub.2 CH.sub.3, Et                                                             161˜3                                                                         1690, 1650, 1540, 1210, 950, 780            135                                                                                ##STR223## COOEt, H    202˜4                                                                         1690, 1545, 1415, 1205, 950, 790            136                                                                                ##STR224## (CH.sub.2).sub.4                                                                          190˜3                                                                         1698, 1541, 1405, 850, 735                  137 (CH.sub.2).sub.2 COOH                                                                     "           236˜7                                                                         1680, 1595, 1530, 1250, 804                 169                                                                                ##STR225## Me, Me      255˜60                                                                        1710, 1670, 1600, 1545, 1250, 970, 785      187                                                                                ##STR226## "           163˜4                                                                         1700, 1680, 1550, 1295, 1155, 780           313                                                                                ##STR227## "           163˜7                                                                         1620, 1550, 1480, 1350, 1210, 940, 850      314                                                                                ##STR228## Me, Me      165˜7                                                                         1655, 1580, 1550, 1385, 950, 780            315                                                                                ##STR229## "           177˜9                                                                         1675, 1550, 1440, 1410, 950, 780            316                                                                                ##STR230## "           242˜6                                                                         1660, 1550, 1405, 945, 775                  317                                                                                ##STR231## "           177˜80                                                                        1660, 1575, 1540, 1430,                                                                               850                 318 NaOOC(CH.sub.2).sub.2                                                                     "           203˜6                                                                         1650, 1630, 1580, 1410, 950, 780            319 NaOOC(CH.sub.2).sub.3                                                                     "           201˜3                                                                         1655, 1555, 1410, 950, 780                  320                                                                                ##STR232## "           167˜70                                                                        1650, 1540, 1440, 1250, 950, 775            321                                                                                ##STR233## "           155˜60                                                                        1660, 1540, 1400, 950, 780                  322                                                                                ##STR234## Et, Me      141˜2                                                                         1660, 1555, 1435, 1350, 945, 780            323                                                                                ##STR235## "           151˜3                                                                         1650, 1560, 1385, 950, 780                  324                                                                                ##STR236## "           150˜5                                                                         1665, 1545, 1405, 955, 780                  325 NaOOC(CH.sub.2).sub.2                                                                     "           194˜6                                                                         1660, 1560, 1410, 945                       326 NaOOC(CH.sub.2).sub.3                                                                     "           205˜10                                                                        1645, 1550, 1410, 950, 830, 780             327                                                                                ##STR237## Et, Me      163˜8 (decompo- sition)                                                       1665, 1550, 1410, 955, 785                  328                                                                                ##STR238## "           180˜5                                                                         1650, 1550, 1405, 1320, 950,                                                                    5 × 10.sup.-9       329                                                                                ##STR239## "           145˜50                                                                        1655, 1545, 1440, 1210, 950, 780            330                                                                                ##STR240## "           145˜50                                                                        1660, 1545, 1410, 1360, 950, 780            331                                                                                ##STR241## "           130˜5                                                                         1650, 1540, 1400, 950, 780                  332                                                                                ##STR242## CH.sub.3 (CH.sub.2).sub.2, Et                                                             153˜7                                                                         1660, 1560, 1440, 950, 850,                                                                     10.sup.-7                 333                                                                                ##STR243## "           195˜7                                                                         1640, 1550, 1383, 950, 780                  334                                                                                ##STR244## "           163˜6                                                                         1655, 1540, 1405, 950, 780                  335 NaOOC(CH.sub.2).sub.2                                                                     "           164˜6                                                                         1660, 1550, 1405, 950, 775                  336 NaOOC(CH.sub.2).sub.3                                                                     "           188˜9                                                                         1650, 1550, 1405, 950, 780                  337                                                                                ##STR245## C.sub.6 H.sub.5, (CH.sub.2).sub.3 CH.sub.3                                                188˜92                                                                        1580, 1550, 1480, 1385, 770, 690            338                                                                                ##STR246## "           153˜5                                                                         1660, 1545, 1480, 1405, 770, 690            339                                                                                ##STR247## Me, (CH.sub.2).sub.3 CH.sub.3                                                             138˜41                                                                        1645, 1545, 1380, 950, 780                  340                                                                                ##STR248## Me, (CH.sub.2).sub.3 CH.sub.3                                                             165˜9                                                                         1660, 1540, 1440, 1405, 960, 780            341 "           (CH.sub.2).sub.2 CH.sub.3, Et                                                             163˜6                                                                         1655, 1540, 1405, 1300, 950, 780            342 "           COOEt, H    177˜80                                                                        1710, 1670, 1545, 1400, 1220, 780           343                                                                                ##STR249## (CH.sub.2).sub.4                                                                          240˜50                                                                        1660, 1550, 1430, 1310, 810                 344 NaOOC(CH.sub.2).sub.2                                                                     "           250˜60                                                                        1665, 1585, 1520, 1400, 950,                __________________________________________________________________________                                      810                                     

                                      TABLE 2-5                                   __________________________________________________________________________     ##STR250##                                                                   Com-                                                                          pound                  m.p.                                                   No.  R.sub.14     Y    (°C.)                                                                         Physical property values.sup.(IR)               __________________________________________________________________________    138                                                                                 ##STR251##  6-OH 304˜6                                                                          1680, 1635, 1510, 1210, 960, 750                139  "            4-Cl 176˜8                                                                          1710, 1660, 1515, 1200, 945, 760                140  "            2-Me 169˜70                                                                         1700, 1650, 1435, 1215, 955, 760                                       (decompo-                                                                     sition)                                                141  "            4-OH 305˜7                                                                          1690, 1640, 1580, 1445, 1260, 760               142  "            4-OMe                                                                              179˜80                                                                         1670, 1430, 1250, 1050, 760                     143  "            6-OMe                                                                              197˜8                                                                          1710, 1635, 1225, 1170, 960, 760                                       (decompo-                                                                     sition)                                                144  "            2-OH 200    3290, 2910, 1690, 1445, 750                                            (decompo-                                                                     sition)                                                145                                                                                 ##STR252##  "    195˜6                                                                          3300, 2950, 1680, 1445, 965, 750                345                                                                                 ##STR253##  6-OH 214˜7                                                                          1610, 1540, 1400, 1240, 955, 750                346  "            4-Cl 168˜72                                                                         1650, 1560, 1400, 1040, 755                     347                                                                                 ##STR254##  2-Me 198˜201                                                                        1635, 1560, 1405, 950, 755                      348  "            4-OH 254˜7                                                                          1680, 1590, 1510, 1200, 820, 760                349  "            4-OMe                                                                              234˜6                                                                          1670, 1565, 1530, 1255, 755                     350  "            6-OMe                                                                              178˜82                                                                         1650, 1550, 1500, 1400, 1235, 1030, 760         351  "            2-OH 240    1680, 1540, 1190, 755                                                  (decompo-                                                                     sition)                                                352                                                                                 ##STR255##  "    200˜5                                                                          1550, 1430, 960, 750                            __________________________________________________________________________

                                      TABLE 2-6                                   __________________________________________________________________________     ##STR256##                                                                                                              Anti-SRS                                                                      action                             Com-                                       [minimum                           pound             m.p.                     effective                          No.   A           (°C.)                                                                      Physical property values .sup.(IR)                                                                 conc. (M)]                         __________________________________________________________________________    146   OCH.sub.2   182˜3                                                                       1700, 1625, 1575, 1490, 755                             147   CH.sub.2 OCH.sub.2                                                                        138˜40                                                                      1700, 1625, 1555, 1530, 953, 753                        148   CONH        217˜9                                                                       1670, 1540, 1290, 1280, 750                             149   CHCHCONH    240˜1                                                                       1705, 1685, 1620, 1580, 1540, 1265, 1160, 750           150   NHCH.sub.2  158˜9                                                                       1690, 1610, 1490, 840, 750                                                                         2 × 10.sup.-7                151   (CH.sub.2).sub.2                                                                          154˜5                                                                       1700, 1620, 1550, 850, 760                              __________________________________________________________________________

    TABLE 2-7      ##STR257##            Anti-SRS      action Com-     [minimum pound   m.p.  effective     No. R.sub.14 R.sub.1 ,R.sub.2 (°C.) Physical property values     conc. (M)]             152      ##STR258##      ##STR259##      151˜3 IR 1700, 1650, 1610, 1490, 1245      153     ##STR260##      " 159˜61 IR 1710, 1640, 1530, 1440, 1180, 750      154     ##STR261##      " -- IR 1710, 1605, 1550, 1200, 730NMR(CDCl.sub.3)2.15˜2.75(6H,m),      2.75˜3.55(4H,m),5.57(2H,d),6.75˜8.10(8H,m)      155 (CH.sub.2).sub.2 COOH " 161˜2 IR 1720, 1660, 1220, 1175, 760     156      ##STR262##      " 158˜9 IR 1687, 1650, 1540, 755      157     ##STR263##      " 163˜4 IR 1720, 1653, 1525, 1185, 755      158     ##STR264##      " 130˜1 IR 1710, 1660, 1540, 1180, 755      159     ##STR265##      " 130˜1 IR 2910, 1690, 1640, 1430      160     ##STR266##      (CH.sub.3).sub.2 CH,H 125˜6 IR 1670, 1600, 1535, 1440, 1210, 780     161      ##STR267##      " 125˜7 IR 1690, 1660, 1545, 1440, 1210, 790      162     ##STR268##      (CH.sub.3).sub.2 CH,H 78˜80 IR 1710, 1660, 1605, 1440, 1175, 780     163      ##STR269##      Et ,Me 149˜50 IR 2920, 1680, 1430, 1190, 785      164     ##STR270##      " 135˜6 IR 1677, 1540, 1430, 1190, 785      165     ##STR271##      " 115˜6 IR 1705, 1655, 1605, 1400, 1175, 790      188 MeOOC     ##STR272##      112˜3 NMR(CDCl.sub.3): δ =      3.3˜3.7(4H,m),3.98(3H,s),6.90˜8.08(8H,m),8.80(1H,broad s)     353      ##STR273##      " 98˜100(decompo-sition) IR 1560, 1435, 860, 760 2 ×     10.sup.-7      354     ##STR274##      " 116˜20 IR 1650, 1580, 1560, 1385, 755      355     ##STR275##      " 223˜7 IR 1660, 1560, 1405, 755      356     ##STR276##      " 201˜10 IR 1660, 1550, 1425, 1200, 755      357 NaOOC(CH.sub.2).sub.2 " 145˜8 IR 1650, 1550, 1420, 750  358      ##STR277##      " 92˜102 IR 1655, 1545, 1435, 755 10.sup.-8      359     ##STR278##      " 80˜85 IR 2950, 1655, 1550, 1430, 955      360     ##STR279##      " 70˜80 IR 2950, 1650, 1550, 1410, 950      361     ##STR280##      ##STR281##      55˜60 IR 2910, 1645, 1545, 1400, 750      362     ##STR282##      CH(CH.sub.3).sub.2,H 96˜98 IR 1650, 1540, 1440, 1205, 735 2     × 10.sup.-8      363     ##STR283##      " 82˜3 IR 1650, 1540, 1400, 1105, 735      364     ##STR284##      " 67˜70 IR 1650, 1540, 1400, 1180, 735      365     ##STR285##      Et ,Me 95˜100 IR 2910, 1650, 1545, 1300, 780      366     ##STR286##      " 75˜80(decompo-sition) IR 2950, 1650, 1540, 1435, 875, 780 5     × 10.sup.-8      367     ##STR287##      " 120˜1(decompo-sition) IR 2950, 1650, 1545, 1435, 1300, 780

                                      TABLE 2-8                                   __________________________________________________________________________     ##STR288##                                                                   Com-                                                                          pound                m.p.                                                     No. A       R.sub.1, R.sub.2                                                                       (°C.)                                                                       Physical property values                            __________________________________________________________________________    171 CHCH    (CH.sub.2).sub.2 CH.sub.3, Et                                                          115˜6                                                                        IR 1705, 1590, 1330, 1190, 940, 678                 172 "       CH(CH.sub.3).sub.2, H                                                                  112˜3                                                                        IR 1690, 1590, 1405, 1185, 945, 775                 173 "                                                                                      ##STR289##                                                                             83˜5                                                                        IR 1670, 1590, 1390, 945, 730                       174 "       Et, Me   129˜30                                                                       IR 1705, 1600, 1330, 1190, 940, 780                 175 "       (CH.sub.2).sub.4 CH.sub.3, H                                                           127˜8                                                                        IR 1700, 1590, 1330, 1180, 965, 715                 176 "       C(CH.sub.3).sub.3, H                                                                   106˜7                                                                        IR 1700, 1600, 1510, 950, 760                       177 "       Et, H    115˜6                                                                        IR 1695, 1590, 1190, 950, 780                       178 "       (CH.sub.2).sub.3 CH.sub.3, H                                                            96˜9                                                                        IR 1705, 1590, 1330, 1190, 945                      179 "       (CH.sub.2).sub.5 CH.sub.3, H                                                           113˜4                                                                        IR 1710, 1600, 1330, 1190, 720                      180 "       (CH.sub.2).sub.6 CH.sub.3, H                                                           108˜9                                                                        IR 1710, 1590, 1330, 720                            181 CH.sub.2 OCH.sub.2                                                                     ##STR290##                                                                             --  IR 1685, 1600, 1100, 755 NMR (CDCl.sub.3):                                    δ = 1.7˜2.7(5H, m), 3.15(2H, t),                                  4.58(2H, s), 4.9(2H, s), 6.4˜8.1(9H, m)       182 OCH.sub.2                                                                             "        120˜3                                                                        IR 1705, 1600, 1250, 1180                           __________________________________________________________________________

                                      TABLE 2-9                                   __________________________________________________________________________     ##STR291##                                                                                                                            Anti-SRS                                                                      action               Com-                                                     [minimum             pound                    m.p.                            effective            No. W            R.sub.1, R.sub.2                                                                      (°C. )                                                                         Physical Property values                                                                              conc.                __________________________________________________________________________                                                             (M)]                 197 EtOOC(CH.sub.2).sub.4                                                                      C.sub.6 H.sub.5,H                                                                     78˜9                                                                            IR 1720, 1480, 1180, 960, 740                198 "            Me, Me  --      IR 1720, 1540, 1440, 1175, 950, 780                                           NMR(CDCl.sub.3): δ = 1.25(3H,t),                                        1.5˜1.9(4H, m),                                                         2.3(s,6H), 2.2˜2.9(m,4H),                                               4.1(2H,q),6.9˜7.4(6H,m)                200 EtOOCCH.sub.2 NH                                                                            ##STR292##                                                                           121˜4                                                                           IR 1720, 1600, 1220, 950, 758                201 EtOOC(CH.sub.2).sub.4 NH                                                                   "       108˜9                                                                           IR 1710, 1595, 1180, 750                     202 "            C.sub.6 H.sub.5,H                                                                     110˜1                                                                           IR 1710, 1595, 1470, 1185, 720               203 EtOOC(CH.sub.2).sub.3 NH                                                                   Me, Me  --      IR 1710, 1595, 1480, 1280, 1190, 755                                          NMR(CDCl.sub.3): δ = 1.25(3H,t),2.0                                     3(2H,m),                                                                      2.35 (6H,s),2.25˜2.50(2H,m),3.20(2H                                     ,m),                                                                          4.16(2H,q),6.28˜7.33(6H,m)             204 EtOOC(CH.sub.2).sub.3 NH                                                                   C.sub.6 H.sub.5,H                                                                     89.5˜90                                                                         NMR(CDCl.sub.3): δ = 1.25(3H,t),1.7                                     8˜2.48(4H,m),                                                           3.20(2H,m),4.13(2H,q),6.38˜8.00(12H                                     ,m)                                          207 EtOOC(CH.sub.2).sub.3 O                                                                     ##STR293##                                                                           135˜7                                                                           IR 1720, 1590, 1273, 1190, 770               208 EtOOC(CH.sub.2).sub.4 O                                                                    "       72˜3                                                                            IR 1720, 1590, 1180, 970, 755                209 EtOOC(CH.sub.2).sub.3 O                                                                    C.sub.6 H.sub.5,H                                                                     85˜86                                                                           IR 1725, 1265, 1180, 945, 730                210                                                                                ##STR294##                                                                                 ##STR295##                                                                           --      IR 1720, 1570, 1140, 950, 760                211                                                                                ##STR296##  "       --      NMR(CDCl.sub.3): δ                                                      = 0.72˜2.97(10H,m), 3.62(3H,s),3.40                                     ˜4.21(2H,m), 6.62˜7.99(10H,m)                                      IR 1720, 1570, 1145, 950, 760               212                                                                                ##STR297##  "       87˜8                                                                            NMR(CCl.sub.4): δ = 1.26(6H,s),1.98                                     (2H,t), 3.62(3H,s),3.92(2H,t), 6.55.about                                     .7.95(10H,m) IR 1710, 1570, 1260, 1040,                                       740                                          373 NaOOC(CH.sub.2).sub.4 NH                                                                   "       239˜40                                                                          IR 2925, 1560, 1430, 1310, 955, 750          374 "            C.sub.6 H.sub.5,H                                                                     270˜1                                                                           IR 2925, 1560, 1430, 960,                                                                             2 ×                                                                     10.sup.-7            375                                                                                ##STR298##                                                                                 ##STR299##                                                                           215˜8                                                                           IR 1570, 1510, 1380, 1280,                                                                            2 ×                                                                     10.sup.-7            394 NaOOC(CH.sub.2).sub.2 O                                                                    "       239˜41                                                                          IR 1570, 1420, 1200, 950, 750                                         (decomposition)                                      395 NaOOC(CH.sub.2).sub.3 O                                                                    "       255˜8                                                                           IR 1550, 1420, 1170, 940,                                                                             5 ×                                                                     10.sup.-7            397 NaOOCCH.sub.2 NH                                                                           "       257˜60                                                                          IR 1595, 1570, 1410, 940, 745                398 NaOOC(CH.sub.2).sub. 4 NH                                                                  "       239˜40                                                                          IR 1595, 1555, 1430, 955, 750                399 "            C.sub.6 H.sub.5,H                                                                     270˜1                                                                           IR 1600, 1560, 1430, 960, 730                401 NaOOCCH.sub.2 O                                                                             ##STR300##                                                                           >320    IR 1590, 1425, 940, 745                      402 NaOOC(CH.sub.2).sub.3 O                                                                    "       260˜2                                                                           IR 1550, 1420, 940, 750                      403 NaOOC(CH.sub.2).sub.3 O                                                                    C.sub.6 H.sub.5,H                                                                     289˜90                                                                          IR 1545, 1415, 950, 730                      404 NaOOC(CH.sub.2).sub.4 O                                                                     ##STR301##                                                                           216˜9                                                                           IR 1560, 1430, 1270, 750                     405                                                                                ##STR302##  "       230 (decomposition)                                                                   IR 2920, 1620, 1560, 1440, 750               406                                                                                ##STR303##  "       198˜203                                                                         IR 1575, 1520, 1480, 1445, 1165, 950,                                         760                                          407                                                                                ##STR304##  "       250 (decomposition)                                                                   IR 1545, 1400, 1200, 1030,                                                                            5 ×                                                                     10.sup.-8            409 NaOOC(CH.sub.2).sub.3                                                                      "       >350    IR 1615, 1425, 1345, 1090, 1070, 823         410 NaOOC(CH.sub.2).sub.4                                                                      "       227˜30                                                                          IR 1560, 1410, 945, 750                      411 NaOOC(CH.sub.2).sub.5                                                                      "       278˜82                                                                          IR 1560, 1430, 1310, 950,                                                                             10.sup.-5            412 NaOOC(CH.sub.2).sub.4                                                                      C.sub.6 H.sub.5,H                                                                     265˜8                                                                           IR 1550, 1440, 960, 730                      413 "            Me, Me  285˜90                                                                          IR 1560, 1410, 950, 765                      431                                                                                ##STR305##  CH(CH.sub.3).sub.2,H                                                                  oil     NMR(CDCl.sub.3): δ = 1.4(6H,s),1.45                                     (6H,d), 1.4(3H,t),2.15(2H,t),2.9˜3.                                     4(1H,m), 3.95˜4.42(4H,m),6.7˜                                     7.42(7H,m) IR 1720, 1590, 1260, 1145,                                         1020                                         432                                                                                ##STR306##  CH(CH.sub.3).sub.2,H                                                                  oil     NMR(CDCl.sub.3): δ = 1.33(6H,d),1.6                                     9(4H,q), 1.85(6H,t),2.07(2H,t),2.80.about                                     . 3.40(1H,m),3.65(3H,s),3.92 (2H,t),6.66.                                     about.7.35(7H,m) IR 1720, 1590, 1240,                                         1140, 1040                                   433                                                                                ##STR307##  "       oil     NMR(CDCl.sub.3): δ = 0.66˜1.1                                     2(6H,m), 1.3˜1.9 (4H,m),1.95˜                                     2.30(2H,t), 3.67(3H,s),3.7˜4.28(2H,                                     m), 6.69˜8.10(10H,m) IR 1720,                                           1240, 1140, 1030, 760                        434                                                                                ##STR308##  "       >300    IR 1580, 1380, 1210, 945,                                                                             2 ×                                                                     10.sup.-8            435                                                                                ##STR309##  "       287˜8                                                                           IR 1610, 1505, 1380, 950,                                                                             10.sup.-7            436                                                                                ##STR310##  "       198˜203                                                                         IR 1575, 1520, 1445, 1040,                                                                            10.sup.-8            438                                                                                ##STR311##  CH(CH.sub.3).sub.2,H                                                                  179˜81                                                                          IR 1690, 1565, 1265, 1025, 965               439                                                                                ##STR312##  CH(CH.sub.3).sub.2,H                                                                  106˜8                                                                           IR 1690, 1590, 1220, 965,                                                                             2 ×                                                                     10.sup.-9            440                                                                                ##STR313##  "       oil     NMR(CDCl.sub.3): δ = 0.92(6H,t),1.3                                     5(6H,d), 1.82(4H,q),2.9˜3.6(1H,m),                                      .35(2H,s),6.4˜7.34(7H,m) IR 1685,                                       1590, 1250, 950, 770                         441                                                                                ##STR314##                                                                                 ##STR315##                                                                           129˜30                                                                          IR 1680, 1585, 1440, 1210,                                                                            5 ×                                                                     10.sup.-8            442                                                                                ##STR316##  "       95˜6                                                                            IR 1665, 1570, 1280, 1200, 950               443                                                                                ##STR317##  (CH.sub.2).sub.2 CH.sub.3,H                                                           64˜5                                                                            IR 1690, 1440, 1260, 955                     444                                                                                ##STR318##  CH(CH.sub.3).sub.2,H                                                                  104˜5                                                                           IR 1700, 1260, 1200, 1150,                   __________________________________________________________________________                                     960                                      

                                      TABLE 2-10                                  __________________________________________________________________________     ##STR319##                                                                                                          Anti-SRS action                        Compound          m.p.                 [minimum effective                     No.   A           (°C.)                                                                       Physical property values (IR)                                                                 conc. (M)]                             __________________________________________________________________________    368   OCH.sub.2   115˜7                                                                        1660, 1560, 1440, 750                                                                         10.sup.-7                              369   CH.sub.2 OCH.sub.2                                                                         67˜70                                                                       1570, 1440, 1355, 750                                                                         10.sup.-5                              370   CONH        277˜80                                                                       1665, 1540, 1435, 1275, 745                            371   CHCHCONH    341˜4                                                                        1670, 1545, 1435, 1260, 1070, 745                      372   NHCH.sub.2  134˜8                                                                        1660, 1560, 1430, 1305, 850, 755                       __________________________________________________________________________

                                      TABLE 2-11                                  __________________________________________________________________________     ##STR320##                                                                   Com-                                       Anti-SRS action                    pound                 m.p.                 [minimum effective                 No. A       R.sub.1, R.sub.2                                                                        (°C.)                                                                       Physical property values (IR)                                                                 conc. (M)]                         __________________________________________________________________________    376 (CH.sub.2).sub.2                                                                       ##STR321##                                                                             148˜50                                                                       2900, 1600, 1550, 1430, 1100,                                                                 5 × 10.sup.-7                377 CHCH    Me, Me    133˜5                                                                        1600, 1555, 1410, 950, 770                                                                    2 × 10.sup.-7                378 "                                                                                      ##STR322##                                                                             179˜82                                                                       1560, 1400, 1305, 940, 770                         379 "                                                                                      ##STR323##                                                                             167˜70                                                                       1625, 1540, 1405, 940, 775                         380 "                                                                                      ##STR324##                                                                             237˜9                                                                        1560, 1410, 1100, 958, 830, 745                    381 "                                                                                      ##STR325##                                                                             205˜7                                                                        1560, 1420, 950, 740, 690                          382 "       Et, Me    144˜6                                                                        1540, 1410, 1330, 950, 765                         383 "       CH(CH.sub.3).sub.2, H                                                                   125˜9                                                                        1560, 1400, 1300, 940, 765                         384 "       (CH.sub.2).sub.4 CH.sub.3, H                                                            165˜70                                                                       1625, 1550, 1405, 950, 768                         385 "       (CH.sub.2).sub.2 CH.sub.3, Et                                                           154˜5                                                                        1555, 1430, 950, 765                               386 CHCH    C(CH.sub.3).sub.3, H                                                                    155˜7                                                                        1560, 1410, 1100, 950, 745                         387 "       Et, H     138˜40                                                                       1550, 1410, 950, 765                                                                          10.sup.-8                          388 "       (CH.sub.2).sub.2 CH.sub.3, H                                                            133˜5                                                                        1555, 1410, 953, 770, 685                          389 "       (CH.sub.2).sub.3 CH.sub.3, H                                                            123˜7                                                                        1595, 1560, 1435, 1410, 955,                                                                  10.sup.-7                          390 "       (CH.sub.2).sub.5 CH.sub.3, H                                                            112˜5                                                                        1560, 1410, 950, 770, 685                          391 "       (CH.sub.2).sub.6 CH.sub.3, H                                                            153˜4                                                                        1550, 1410, 950, 770                               392 OCH.sub.2                                                                              ##STR326##                                                                             125˜30                                                                       1615, 1570, 1210, 753                              393 CH.sub.2 OCH.sub.2                                                                    "         139˜45                                                                       1675, 1600, 1460, 1400, 755                        400 CHCH    C.sub.6 H.sub.5, H                                                                      270˜6                                                                        1600, 1550, 1430, 955, 730                         __________________________________________________________________________

                                      TABLE 2-12                                  __________________________________________________________________________    Com-                                                                          pound                              m.p.                                       No. Structural Formula             (°C.)                                                                      Physical property values               __________________________________________________________________________                                           (IR)                                   205                                                                                ##STR327##                     98˜9                                                                       1715, 1600, 1250, 1175, 750            408                                                                                ##STR328##                    207˜8                                                                       1557, 1430, 1165, 1040, 750            420                                                                                ##STR329##                    224˜5                                                                       1660, 1520, 1440, 750                  421                                                                                ##STR330##                    108˜9                                                                       1570, 1430, 1085,                      __________________________________________________________________________                                           750                                

                  TABLE 3                                                         ______________________________________                                                         Anti-SRS action                                              Test compound    [Minimum effective conc.                                     Compound    Example  (M)]                                                     ______________________________________                                        1           1        5 × 0.sup.-8                                       189         9        10.sup.-6                                                199         13       2 × 10.sup.-7                                      213         17       5 × 10.sup.-8                                      398         19       2 × 10.sup.-7                                      414         21       10.sup.-6                                                422         23       10.sup.-6                                                423         24       10.sup.-5                                                424         25       5 × 10.sup.-7                                      426         27       2 × 10.sup.-7                                      ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                                             Airway resistance                                        Test Compound        increase inhibition                                      Compound No. Dosage (mg/kg)                                                                            (%)                                                  ______________________________________                                        213          30          51                                                   223          3           87                                                   227          3           71                                                   272          10          37                                                   297          10          62                                                   353          30          79                                                   396          3           55                                                   ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                                       Acute toxicity value                                           Compound No.   (LD.sub.50 mg/kg)                                              ______________________________________                                        2              >3000                                                          26             >3000                                                          213            >3000                                                          216            >3000                                                          232            3000                                                           247            >3000                                                          248            >3000                                                          249            1000 ˜ 2000                                              281            >3000                                                          300            1000 ˜ 2000                                              303            2000                                                           313            1560                                                           314            2000 ˜ 3000                                              315            1000 ˜ 2000                                              317            1032                                                           324            1380                                                           325            2000                                                           326            <3000                                                          353            3308                                                           355            1928                                                           382            1928                                                           396            2000 ˜ 3000                                              418            <3000                                                          ______________________________________                                    

We claim:
 1. A thiazole derivative represented by the following formulaand a pharmaceutically acceptable salt thereof: ##STR331## wherein R₁and R₂ each independently represent a hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, a lower alkoxycarbonyl group or a phenylgroup which is unsubstituted or substituted with a halogen atom, a loweralkoxy group, a lower alkoxycarbonyl group or an alkyl group of 1 to 3carbon atoms or wherein R₁ and R₂ cooperate to represent atetramethylene group corresponding to a fused cyclohexane ring or abutadienylene group which is unsubstituted or substituted with a halogenatom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkylgroup having 1 to 3 carbon atoms corresponding to a fused benzene ring;R₃, R₄, R₅ and R₆ each independently represent a hydrogen atom, ahydroxyl group, a lower alkoxy group, an alkyl group having 1 to 3carbon atoms or a halogen atom; A is a linking group selected from thegroup consisting of --CH═CH--, --CH₂ CH₂ --, --CH═CHCONH-- and -- CH₂OCH₂ --; B is a group selected from the group consisting of (a)--(CH₂)_(n) --CONH--, wherein n is an integer of 0-3, (b) --(CH₂)_(n)--NH--, wherein n is an integer of 1-4, (c) --(CH₂)_(n) --O--, wherein nis an integer of 1-4, (d) --(CH₂)_(n) --, wherein n is an integer of2-5, ##STR332## wherein R₇ and R₈ each independently represents ahydrogen atom or an alkyl group having 1 to 3 carbon atoms as definedabove, ##STR333## wherein R₇ and R₈ have the same meanings as definedabove, ##STR334## wherein R₇ and R₈ have the same meanings as definedabove, ##STR335## wherein R₉, R₁₀, R₁₁ and R₁₂ each independentlyrepresent a hydrogen atom, a phenyl group or an alkyl group having 1 to6 carbon atoms, ##STR336## wherein R₉, R₁₀, R₁₁ and R₁₂ have the samemeanings as defined above, ##STR337## wherein R₉, R₁₀, R₁₁ and R₁₂ havethe same meanings as defined above and m ranges from 0 to 3, ##STR338##wherein R₉ and R₁₁ have the same meanings as defined above, ##STR339##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR340##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR341##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR342##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR343##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR344##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR345##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR346##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR347##wherein R₁₁ and R₁₂ have the same meanings as defined above, and##STR348## wherein R₁₁ and R₁₂ have the same meanings as defined aboveand Q represents a carboxyl group, a lower alkoxy group, a hydroxylgroup, an alkoxycarbonyl group having 2 to 6 carbon atoms or a5-tetrazolyl group.
 2. The thiazole derivative and the pharmaceuticallyacceptable salt thereof according to claim 1, wherein said group B hasthe formkla: ##STR349## wherein R₉ and R₁₀ each independently representan alkyl group of 1 to 6 carbon atoms.
 3. A leukotriene antagonistcomposition comprising:a pharmaceutically effective amount of a thiazolederivative represented by the following formula or a pharmaceuticallyacceptable salt thereof as the active ingredient: ##STR350## wherein R₁and R₂ each independently represent a hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, a lower alkoxycarbonyl group or a phenylgroup which is unsubstituted or substituted with a halogen atom, a loweralkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1 to3 carbon atoms or wherein R₁ and R₂ cooperate to represent atetramethylene group corresponding to a fused cyclohexane ring or abutadienylene group which is unsubstituted or substituted with a halogenatom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkylgroup having 1 to 3 carbon atoms corresponding to a fused benzene ring;R₃, R₄, R₅ and R₆ each independently represent a hydrogen atom, ahydroxyl group, a lower alkoxy group, an alkyl group having 1 to 3carbon atoms or a halogen atom; A is a linking group selected from thegroup consisting of --CH═CH--, --CH₂ CH₂ --, --CH═CHCONH-- and --CH₂OCH₂ --; B is a group selected from the group consisting of (a)--(CH₂)_(n) --CONH--, wherein n is an integer of 1-3, (b) --(CH₂)_(n)--NH--, wherein n is an integer of 1-4, (c) --(CH₂)_(n) --O--, wherein nis an integer of 1-4, (d) --(CH₂)_(n) --, wherein n is an integer of2-5, ##STR351## wherein R₇ and R₈ each independently represent ahydrogen atom or an alkyl group having 1 to 3 carbon atoms as definedabove, ##STR352## wherein R₇ and R₈ have the same meanings as definedabove, ##STR353## wherein R₇ and R₈ have the same meanings as definedabove, ##STR354## wherein R₉, R₁₀, R₁₁ and R₁₂ each independentlyrepresent a hydrogen atom, a phenyl group or an alkyl group having 1 to6 carbon atoms, ##STR355## wherein R₉, R₁₀, R₁₁ and R₁₂ have the samemeanings as defined above, ##STR356## wherein R₉, R₁₀, R₁₁ and R₁₂ havethe same meanings as defined above and m ranges from 0 to 3, ##STR357##wherein R₉ and R₁₁ have the same meanings as defined above, ##STR358##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR359##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR360##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR361##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR362##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR363##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR364##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR365##wherein R₁₀ and R₁₂ have the same meanings as defined above, ##STR366##wherein R₁₁ and R₁₂ have the same meanings as defined above, and##STR367## wherein R₁₁ and R₁₂ have the same meanings as defined above;and Q represents a carboxyl group, a lower alkoxy group, a hydroxylgroup, an alkoxycarbonyl group having 2 to 6 carbon atoms or a5-tetrazolyl group, in combination with a pharmaceutically acceptableexcipient.
 4. The leukotriene antagonist composition of claim 3, whereinsaid group B has the formula: ##STR368## wherein R₉ and R₁₀ eachindependently represent an alkyl group of 1 to 6 carbon atoms.
 5. Aleukotriene antagonist composition, comprising:a pharmaceuticallyeffective amount of a thiazole derivative represented by the followingformula or a pharmaceutically acceptable salt thereof as the activeingredient: ##STR369## wherein R₇ and R₈ each independently represent ahydrogen atom, an alkyl group having 1-8 carbon atoms or cooperativelyrepresent a butadienylene group which is unsubstituted or substitutedwith a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl groupor an alkyl group having 1-3 carbon atoms corresponding to a fusedbenzene ring; and R₉ and R₁₀ each independently represent a hydrogenatom or an alkyl group having 1-6 carbon atoms.
 6. A method oftherapeutically treating an allergic disorder in which leukotriene isreleased, comprising: administering to a host subject a leukotrieneantagonistic effective amount of the thiazole derivative of claim 1.